Compounds comprising heterocyclic-substituted piperidine for treating pain

ABSTRACT

The invention relates to Heterocyclic-Substituted Piperidine Compounds, compositions comprising an effective amount of a Heterocyclic-Substituted Piperidine Compound and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Heterocyclic-Substituted Piperidine Compound.

This application is a continuation of PCT application no.PCT/US08/51096, filed Jan. 15, 2008, which claims the benefit under 35U.S.C. §119(e) of U.S. provisional application No. 60/880,955, filedJan. 16, 2007, and U.S. provisional application No. 60/930,035, filedMay 11, 2007, the contents of all of which are incorporated herein byreference.

1. FIELD OF THE INVENTION

The invention relates to Heterocyclic-Substituted Piperidine Compounds,compositions comprising an effective amount of aHeterocyclic-Substituted Piperidine Compound and methods to treat orprevent a condition, such as pain, comprising administering to an animalin need thereof an effective amount of a Heterocyclic-SubstitutedPiperidine Compound.

2. BACKGROUND OF THE INVENTION

Chronic pain is a major contributor to disability and is the cause ofmuch suffering. The successful treatment of severe and chronic pain is aprimary goal of the physician, with opioid analgesics being preferreddrugs for doing so.

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes are known as μ, δ and κ. Asopiates have a high affinity for these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as enkephalins, endorphins and dynorphins.

Recent experimentation has led to the identification of a cDNA encodingan opioid receptor-like (ORL-1) receptor with a high degree of homologyto the known receptor classes. The ORL-1 receptor was classified as anopioid receptor based only on structural grounds, as the receptor didnot exhibit pharmacological homology. It was initially demonstrated thatnon-selective ligands having a high affinity for μ, δ and κ, receptorshad low affinity for the ORL-1 receptor. This characteristic, along withthe fact that an endogenous ligand had not yet been discovered, led tothe term “orphan receptor”.

Subsequent research led to the isolation and structure of the endogenousligand of the ORL-1 receptor (i.e., nociceptin). This ligand is aseventeen amino acid peptide structurally similar to members of theopioid peptide family.

The discovery of the ORL-1 receptor presents an opportunity in drugdiscovery for novel compounds that can be administered for painmanagement or other syndromes modulated by this receptor.

The publications “From Hit to Lead: Combining Two Complementary Methods”and “From Hit to Lead: Analyzing Structure-Profile Relationships” ofPoulain et al. (J. Med. Chem. 44:3378-3390 and 3391-3401, respectively(2001)) describe carbamates and carbamate analogs for use as opioidreceptor ligands.

International PCT Publication No. WO 95/03299 describes benzodiazepinederivatives for use as CCK or gastrin antagonists.

International PCT Publication No. WO 00/06545 A1 describes piperidinederivatives as high affinity ligands for the nociceptin receptor ORL-1.

International PCT Publication No. WO 01/07050 A1 describes substitutedpiperidines as nociceptin receptor ORL-1 agonists for use to treatcough.

International PCT Publication No. WO 01/34571 describes β-amino acidcompounds for use in inhibiting β-amyloid peptide release.

International PCT Publication No. WO 02/080895 A2 describes farnesylprotein transferase inhibitors comprising bicyclic groups for use intreating malaria.

U.S. published patent application No. US 2003/0134846 by Windsor et al.describes farnesyl protein transferase inhibitors, some of whichcomprise bicyclic groups, for use in treating Trypanosoma Bruceiinfection.

U.S. published patent application No. US 2003/0149027 by Oi et al.describes benzodiazepine compounds for use in regulating somatostatinreceptors.

U.S. published patent application No. US 2003/0207886 by Plücker et al.describes quinoxaline derivatives for use in protecting human epidermisor hair against uv radiation.

U.S. published patent application No. US 2004/0082784 by Sielecki-Dzurdzet al. describes pyridino and pyrimidino pyrazinones for use ascorticotropin releasing factor receptor antagonists to treat anxiety anddepression.

U.S. published patent application No. US 2004/0220177 by Kath et al.describes pyrimidine derivatives for use in treating abnormal cellgrowth in cancer.

Japanese Application No. JP 08/291,071 A2 and U.S. Pat. No. 5,283,244 bySakamoto et al. each describe fused pyrazine derivatives for use,respectively, as stable injection solutions and glutamate antagonists.

U.S. Pat. Nos. 5,739,129 and 5,859,007 by Aquino et al. describebenzodiazepine derivatives for use as CCK or gastrin modulators.

U.S. Pat. Nos. 6,576,644 and 6,835,737 by Bi et al. describeaminoquinolines for use as inhibitors of cGMP phosphodiesterase.

U.S. Pat. No. 7,001,901 by Yang describes tetrazolylpropionamides foruse as inhibitors of Aβ protein production.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY OF THE INVENTION

It is an object of the invention to provide new compounds that exhibitaffinity for the ORL-1 receptor.

In certain embodiments of the invention, such new compounds exhibitagonist activity at the ORL-1 receptor.

In certain other embodiments of the invention, such new compoundsexhibit antagonist activity at the ORL-1 receptor.

In certain embodiments of the invention, such new compounds exhibitaffinity for the ORL-1 receptor, and also for one or more of the μ, δ orκ receptors. In a particular embodiment, a new compound of the inventionexhibits affinity for both the ORL-1 receptor and the μ receptor. In amore specific embodiment, a new compound of the invention acts as anORL-1 receptor antagonist and as a μ receptor agonist.

Certain new compounds of the invention can be used to treat an animalsuffering from chronic or acute pain.

It is a further object of the invention to provide methods of treatingchronic or acute pain in an animal by administering one or moreHeterocyclic-Substituted Piperidine Compounds of the invention to ananimal in need of such treatment. In certain embodiments, such newHeterocyclic-Substituted Piperidine Compounds effectively treat chronicor acute pain in the animal, while producing fewer or reduced sideeffects compared to previously available compounds.

The invention encompasses compounds of formula (I):

and pharmaceutically acceptable derivatives thereof wherein:

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂),        —N(T₃)C(O)T₃, —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or        —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₈ groups; or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthalenyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T₁)(T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,        —(C₂-C₆)alkynyl or —(C₁-C₆)alkoxy, each of which        —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl or —(C₂-C₆)alkynyl is unsubstituted or        substituted with 1 or 2 substituents independently selected from        —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,        —N(R₆)C(O)R₅ and -(5- or 6-membered)heterocycle or 1, 2 or 3        independently selected -halo; or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₅ groups, and        which bridge optionally contains —HC═CH— within the        (C₂-C₆)bridge; wherein the piperazine ring that is fused to the        phenyl group can be in the endo- or exo-conformation with        respect to the A-B bridge; or    -   (c) A-B together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the piperazine ring that is fused to the phenyl group can be inthe endo- or exo-conformation with respect to the A-B bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R₆)S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))—(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))—(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

each R_(b) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsindependently selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃,—C(O)N(R₆)₂, —N(R₆)C(O)R₅ and -(5- or 6-membered)heterocycle or from 1to 3 independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 independently selected R₈ groups and, optionally, in        which any D group carbon atom except the carbon atom bonded        directly to the piperidine or bridged piperidine central ring,        is independently replaced by O or S; or    -   (c) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

Z is a bond;

R₁ is selected from:

m is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

e and f are each an integer independently selected from 0, 1, 2, 3, 4 or5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3 or 4provided that 1≦+k)≦4;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups and, optionally, in which any carbon atom is independentlyreplaced by O or S, or T₁ and T₂ together can form a 5- to 8-memberedring where the number of atoms in the ring includes the nitrogen atom towhich T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstitutedor substituted with 1, 2 or 3 independently selected R₈ groups and,optionally, any carbon atom in said 5- to 8-membered ring isindependently replaced by O or S;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -phenyl, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each p is an integer independently selected from 0 or 1;

R₁₁ is selected from —H, —C(O)OR₉, —C(O)N(R₆)₂, or —(C₁-C₄)alkyl whichis unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂; and

each halo is independently selected from —F, —Cl, —Br, or —I.

The invention encompasses compounds of formula (II):

and pharmaceutically acceptable derivatives thereof wherein:

Q is selected from naphthaleno or pyridino;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂),        —N(T₃)C(O)T₃, —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or        —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₈ groups; or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthalenyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T₁)(T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,        —(C₂-C₆)alkynyl or —(C₁-C₆)alkoxy, each of which        —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl or —(C₂-C₆)alkynyl is unsubstituted or        substituted with 1 or 2 substituents independently selected from        —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,        —N(R₆)C(O)R₉ and -(5- or 6-membered)heterocycle or 1, 2 or 3        independently selected -halo; or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₈ groups, and        which bridge optionally contains —HC═CH— within the        (C₂-C₆)bridge; wherein the piperazine ring that is fused to the        Q group can be in the endo- or exo-conformation with respect to        the A-B bridge; or    -   (c) A-B together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the piperazine ring that is fused to the Q group can be in theendo- or exo-conformation with respect to the A-B bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))—(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))—(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsindependently selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃,—C(O)N(R₆)₂, —N(R₆)C(O)R₉ and -(5- or 6-membered)heterocycle or from 1to 3 independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 independently selected R₈ groups and, optionally, in        which any D group carbon atom except the carbon atom bonded        directly to the piperidine or bridged piperidine central ring is        independently replaced by O or S; or    -   (c) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)-, where h is 0 or1; or —(C₁-C₁₀)alkyl-NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -phenyl, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, R₁₁ is selected from —H, —C(O)OR₉, —C(O)N(R₆)₂, or—(C₁-C₄)alkyl which is unsubstituted or substituted with —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂;

if h is 1, R₁ is selected from —H, —OH, -halo, —C(O)OR₉, —C(O)N(R₆)₂, or—(C₁-C₄)alkyl which is unsubstituted or substituted with —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

e and f are each an integer independently selected from 0, 1, 2, 3, 4 or5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3 or 4provided that 1≦+k)≦4;

each p is an integer independently selected from 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₅groups and, optionally, in which any carbon atom is independentlyreplaced by O or S, or T₁ and T₂ together can form a 5- to 8-memberedring where the number of atoms in the ring includes the nitrogen atom towhich T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstitutedor substituted with 1, 2 or 3 independently selected R₈ groups and,optionally, any carbon atom in said 5- to 8-membered ring isindependently replaced by O or S;

-   -   each V₁ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is 0, then R₁ is not -halo or —NO₂;

provided that when Q is pyridino, then R₂ is not imidazolyl ortriazolyl;

provided that when Q is pyridino and R₂ is -phenyl, -naphthalenyl, or-(5- or 6-membered)heteroaryl, then the R₂ group is not attached to apyridino atom bonded to a 5- or 6-position carbon atom; and

provided that R₃ does not include an imidazolyl group.

The invention encompasses compounds of formula (III):

and pharmaceutically acceptable derivatives thereof wherein:

Q is selected from benzo, naphthaleno, (C₁₄)aryl, (C₃-C₁₂)cycloalkyl,(C₆-C₁₄)bicycloalkyl, (C₅-C₁₀)cycloalkenyl, (C₇-C₁₄)bicycloalkenyl, (3-to 7-membered)heterocycle, or (5- to 10-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂),        —N(T₃)C(O)T₃, —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or        —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₈ groups; or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthalenyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

X is —C(R₄)(R₅)—, —N(R₁₃)—, —C(R₄)(R₅)—C(R₄′)(R₅′)—, —C(R₄)═C(R₄′)—,—C(R₄)(R₅)—N(R₁₃)—, or —N(R₁₃)—C(R₄)(R₅)—;

each R₄ and R₄′ is independently selected from —H, —OR₆, —(C₁-C₆)alkyl,or —(C₃-C₇)cycloalkyl; or, independently, any two of R₄ and R₅, or R₄′and R₅′, together can form an oxo group; or any two of R₄ and R₄′ canform a 4- to 8-membered cycloalkyl ring, the number of atoms in the ringincluding the atoms to which the two of R₄ and R₄′ are attached and anyintervening atoms, if present;

each R₅ and R₅′ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl;

R₁₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₉-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups; or    -   (d) —C(O)O(C₃-C₈)cycloalkyl, —CH₂CH₂OH, —(C₁-C₆)alkyl(═O)W₂, or        —(C₁-C₆)alkyl-W₂; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —N(R₆)₂; —C(O)OR₉; —C(O)N(R₉)₂;        —OC(O)(C₃-C₈)cycloalkyl; —NHS(O)₂(C₃-C₈)cycloalkyl; —NHC(O)W₂;        —NHS(O)₂W₂; —(C₃-C₁₂)cycloalkyl, —(C₃-C₇)cycloalkenyl,        —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or further substituted with 1, 2 or 3 independently selected R₈        groups; or -phenyl, -naphthalenyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        further substituted with 1, 2 or 3 independently selected R₈        groups;

each W₂ is independently selected from —(C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, (3- to 7-membered)heterocycle,—CH₂CH₂OH, and —N(R₆)₂;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T)I (T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,        —(C₂-C₆)alkynyl or —(C₁-C₆)alkoxy, each of which        —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl or —(C₂-C₆)alkynyl is unsubstituted or        substituted with 1 or 2 substituents independently selected from        —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,        —N(R₆)C(O)R₉ and -(5- or 6-membered)heterocycle or 1, 2 or 3        independently selected -halo; or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₈ groups, and        which bridge optionally contains —HC═CH— within the        (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to        the Q group can be in the endo- or exo-conformation with respect        to the A-B bridge; or    -   (c) A-B together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the heterocyclic ring that is fused to the Q group can be in theendo- or exo-conformation with respect to the A-B bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))—(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))—(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsindependently selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃,—C(O)N(R₆)₂, —N(R₆)C(O)R₉ and -(5- or 6-membered)heterocycle or from 1to 3 independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 independently selected R₈ groups and, optionally, in        which any D group carbon atom except the carbon atom bonded        directly to the piperidine or bridged piperidine central ring,        is independently replaced by O or S; or    -   (c) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)-, where h is 0 or1; or —(C₁-C₁₀)alkyl-NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN;    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy; —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -phenyl, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, R₁ is selected from —H, —C(O)OR₉, —C(O)N(R₆)₂, or—(C₁-C₄)alkyl which is unsubstituted or substituted with —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂;

if h is 1, R₁ is selected from —H, —OH, -halo, —C(O)OR₉, —C(O)N(R₆)₂, or—(C₁-C₄)alkyl which is unsubstituted or substituted with —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

e and f are each an integer independently selected from 0, 1, 2, 3, 4 or5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3 or 4provided that 1≦(j+k)≦4;

each p is an integer independently selected from 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₅groups and, optionally, in which any carbon atom is independentlyreplaced by O or S, or T₁ and T₂ together can form a 5- to 8-memberedring where the number of atoms in the ring includes the nitrogen atom towhich T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstitutedor substituted with 1, 2 or 3 independently selected R₈ groups and,optionally, any carbon atom in said 5- to 8-membered ring isindependently replaced by O or S;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is 0, then R₁ is not -halo or —NO₂;

provided that when Q is benzo, then X is not —N(R₁₃)—;

provided that when Q is benzo, then R₃ is not —(C₁-C₂)alkyl substitutedwith —C(O)N(V₁)₂; and

provided that R₃ does not include an imidazolyl group.

The invention encompasses compounds of formula (IV):

and pharmaceutically acceptable derivatives thereof wherein:

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂),        —N(T₃)C(O)T₃, —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or        —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₈ groups; or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthalenyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

R₁₂ is selected from:

-   -   (a) —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, each        of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₈ groups; or    -   (b) —(C₁₄)aryl which is unsubstituted or substituted with 1, 2        or 3 independently selected R₇ groups; or    -   (c) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —C(O)OR₉, —C(O)N(R₉)₂,        —(C₃-C₁₂)cycloalkyl which is unsubstituted or further        substituted with 1, 2 or 3 independently selected R₈ groups,        —(C₃-C₁₂)cycloalkoxy which is unsubstituted or further        substituted with 1, 2 or 3 independently selected R₈ groups,        -(3- to 7-membered)heterocycle which is unsubstituted or further        substituted with 1, 2 or 3 independently selected R₈ groups, or        —(C₁₄)aryl which is unsubstituted or further substituted with 1,        2 or 3 independently selected R₇ groups; or    -   (d) —C(O)O(C₃-C₈)cycloalkyl, —CH₂CH₂OH,        —C(O)N(V₁)(C₃-C₈)cycloalkyl, —(C₁-C₆)alkyl(═O)W₂, or        —(C₁-C₆)alkyl-W₂; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —OC(O)(C₃-C₈)cycloalkyl,        —NHS(O)₂(C₃-C₈)cycloalkyl, —N(V₁)C(O)(C₃-C₈)cycloalkyl,        —NHC(O)W₂, and —NHS(O)₂W₂;

each W₂ is independently selected from —(C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, (3- to 7-membered)heterocycle,—CH₂CH₂OH, and —N(R₆)₂;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T₁)(T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,        —(C₂-C₆)alkynyl or —(C₁-C₆)alkoxy, each of which        —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl or —(C₂-C₆)alkynyl is unsubstituted or        substituted with 1 or 2 substituents independently selected from        —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,        —N(R₆)C(O)R₅ and -(5- or 6-membered)heterocycle or 1, 2 or 3        independently selected -halo; or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₈ groups, and        which bridge optionally contains —HC═CH— within the        (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to        the phenyl group can be in the endo- or exo-conformation with        respect to the A-B bridge; or    -   (c) A-B together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the heterocyclic ring that is fused to the phenyl group can bein the endo- or exo-conformation with respect to the A-B bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))—(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl, —N(R₆)—(C₁₄)aryl,        or —N(R_(c))—(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsindependently selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃,—C(O)N(R₆)₂, —N(R₆)C(O)R₅ and -(5- or 6-membered)heterocycle or from 1to 3 independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 independently selected R₈ groups and, optionally, in        which any D group carbon atom except the carbon atom bonded        directly to the piperidine or bridged piperidine central ring,        is independently replaced by O or S; or    -   (c) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)-, where h is 0 or1; or —[(C₁-C₁₀)alkyl]NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

-   -   each R₈ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, oxo, ═S, -phenyl, -halo, —N₃, —NO₂,        —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉, —S(O)R₉, or        —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, R₁₁ is selected from —H, —C(O)OR₉, —C(O)N(R₆)₂, or—(C₁-C₄)alkyl which is unsubstituted or substituted with —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂;

if h is 1, R₁₁ is selected from —H, —OH, -halo, —C(O)OR₉, —C(O)N(R₆)₂,or —(C₁-C₄)alkyl which is unsubstituted or substituted with —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

e and f are each an integer independently selected from 0, 1, 2, 3, 4 or5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3 or 4provided that 1≦+k)≦4;

each p is an integer independently selected from 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups and, optionally, in which any carbon atom is independentlyreplaced by O or S, or T₁ and T₂ together can form a 5- to 8-memberedring where the number of atoms in the ring includes the nitrogen atom towhich T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstitutedor substituted with 1, 2 or 3 independently selected R₈ groups and,optionally, any carbon atom in said 5- to 8-membered ring isindependently replaced by O or S;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is 0, R₁ is not -halo or —NO₂.

A compound of formula (I), (II), (III) or (IV) or a pharmaceuticallyacceptable derivative thereof (a “Heterocyclic-Substituted PiperidineCompound”) is useful, e.g., as an analgesic, anti-inflammatory,diuretic, anesthetic agent, neuroprotective agent, anti-hypertensive, ananxiolytic agent, an agent for appetite control, hearing regulator,anti-tussive, anti-asthmatic, modulator of locomotor activity, modulatorof learning and memory, regulator of neurotransmitter release, regulatorof hormone release, kidney function modulator, anti-depressant, agent totreat memory loss due to Alzheimer's disease and/or other dementias,anti-epileptic, anti-convulsant, agent to treat withdrawal from alcohol,agent to treat withdrawal from drug(s) of addiction, agent to controlwater balance, agent to control sodium excretion, and/or agent tocontrol arterial blood pressure disorder(s).

A Heterocyclic-Substituted Piperidine Compound is useful for treatingand/or preventing pain, anxiety, cough, diarrhea, high blood pressure,epilepsy, anorexia/cachexia, urinary incontinence, drug abuse, a memorydisorder, obesity, constipation, depression, dementia, or Parkinsonism(each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effectiveamount of a Heterocyclic-Substituted Piperidine Compound and apharmaceutically acceptable carrier or excipient. The compositions areuseful for treating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition,comprising administering to an animal in need thereof an effectiveamount of a Heterocyclic-Substituted Piperidine Compound.

The invention further relates to methods for preventing a Condition,comprising administering to an animal in need thereof an effectiveamount of a Heterocyclic-Substituted Piperidine Compound.

The invention further relates to a Heterocyclic-Substituted PiperidineCompound for use as a medicament.

The invention further relates to the use of a Heterocyclic-SubstitutedPiperidine Compound, e.g., of Formulas (I), (II), (III) and/or (IV), forthe manufacture of a medicament useful for treating a Condition.

The invention further relates to the use of a Heterocyclic-SubstitutedPiperidine Compound, e.g., of Formulas (I), (I), (III) and/or (IV), forthe manufacture of a medicament useful for preventing a Condition.

The invention still further relates to methods for inhibiting ORL-1receptor function in a cell, comprising contacting a cell capable ofexpressing the ORL-1 receptor with an ORL-1 receptor function inhibitingamount of a Heterocyclic-Substituted Piperidine Compound.

The invention still further relates to methods for activating ORL-1receptor function in a cell, comprising contacting a cell capable ofexpressing the ORL-1 receptor with an ORL-1 receptor function activatingamount of a Heterocyclic-Substituted Piperidine Compound.

The invention still further relates to methods for preparing acomposition, comprising the step of admixing a Heterocyclic-SubstitutedPiperidine Compound and a pharmaceutically acceptable carrier orexcipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a Heterocyclic-Substituted PiperidineCompound.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention. Other objects andadvantages of the invention will become apparent from the followingdetailed description thereof.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Heterocyclic-SubstitutedPiperidine Compounds of Formula (I)

As stated above, the invention encompasses Heterocyclic-SubstitutedPiperidine Compounds of Formula (I):

and pharmaceutically acceptable derivatives thereof where R₁, R₂, R₃, Y,Z, A, B, C, D, a and the dashed line are defined above for theHeterocyclic-Substituted Piperidine Compounds of Formula (I).

In one embodiment, each Y is O.

In another embodiment, each Y is S.

In another embodiment, A is H.

In another embodiment, B is H.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups, and which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge; wherein the piperazine ring that is fused to the phenylgroup can be in the endo- or exo-conformation with respect to the A-Bbridge.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted and which bridge optionally contains —HC═CH— within the(C₂-C₃)bridge; wherein the piperazine ring that is fused to the phenylgroup can be in the endo- or exo-conformation with respect to the A-Bbridge.

In another embodiment, A-B together form a (C₂)bridge, a —HC═CH— bridge,or a (C₃)bridge each of which is unsubstituted; wherein the piperazinering that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, C is H.

In another embodiment, D is H.

In another embodiment, a is 0 or 1.

In another embodiment, a is 0.

In another embodiment, a is 1.

In another embodiment, a is 2.

In another embodiment, each Y is O, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is O, A, B, C and D are each H, and a is0.

In another embodiment, each Y is S, A, B, C and D are each H, and a is0.

In another embodiment, each Y is O, A, B, C and D are each H, and a is1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₅ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₉ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₅ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 1.

In another embodiment, R₃ is —H, —(C₁-C₆)alkyl, —(C₁-C₆)alkylsubstituted by an R₈ group, —(C₃-C₇)cycloalkyl, or —(C₃-C₇)cycloalkylsubstituted by an R₈ group.

In another embodiment, R₃ is —H, —C(O)OV₁, —C(O)N(V₁)₂, or —(C₁-C₂)alkylsubstituted with a substituent selected from —NHS(O)₂W₁, —C(O)OV₁, and—C(O)N(V₁)₂.

In another embodiment, R₃ is —H.

In another embodiment, R₃ is —(C₁-C₆)alkyl.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by an R₈ group.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by —CN.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by an R₈ group.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by —CN.

In another embodiment, R₃ is —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is cyclopentyl, cyclohexyl, or cycloheptyl.

In another embodiment, R₃ is —H or methyl substituted by —CN.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each R₂ is independently -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, each R₂ is independently -halo.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl,cycloheptyl, or phenyl.

In another embodiment, a is 2 and each R₂ is independently -halo.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN, methyl,ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl, cycloheptyl, orphenyl.

In another embodiment, a is 1 and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1,and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, a is 1, and R₂ is -halo, optionally—F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 0,and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 0, and R₃ is methyl, ethyl,n-propyl or iso-propyl, each of which is substituted by an R₈ group, or—H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, a is 0, and R₃ is methyl, ethyl,n-propyl or iso-propyl, each of which is substituted by an R₈ group, or—H.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1, R₂is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, R₂ is -halo, optionally —F, andR₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, a is 1, R₂ is -halo, optionally —F,and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, R₁ is selected from:

In another embodiment, R₁ is selected from formula (i) and m is 5.

In another embodiment, R₁ is selected from formula (i), m is 5, and p is0.

In another embodiment, R₁ is selected from formula (i), m is 5, p is 0,and R₁₁ is —H.

In another embodiment, R₁ is selected from formula (i) and m is 3.

In another embodiment, R₁ is selected from formula (i), m is 3, and p is1.

In another embodiment, R₁ is selected from formula (i), m is 3, p is 1,and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, R₁ is selected from formula (i), m is 3, R₁ is—H, p is 1, and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, R₁ is selected from formula (iii) and j+k=1.

In another embodiment, R₁ is selected from formula (iii), j+k=1, and pis 0.

In another embodiment, R₁ is selected from:

where m is an integer selected from 3, 4 or 5;

j is an integer selected from 1 or 2;

k is 0; and

each p is an integer independently selected from 0 or 1.

In another embodiment, each p is 0.

In another embodiment, in formulas (ia) and (ib) p is 1 and R₈ isselected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3, p is 1, and R₈is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 5, p is 1, and R₉is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3 and p is 0.

In another embodiment, in formulas (ia) and (ib) m is 5 and p is 0.

In another embodiment, in formula (iii) one p is 0, the other p is 1,and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formula (iii) j is 1 and each p is 0.

In another embodiment, in formula (iii) j is 1, one p is 0, the other pis 1, and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, the Heterocyclic-Substituted Piperidine Compoundof Formula (I) is

In another embodiment, the Heterocyclic-Substituted Piperidine Compoundof Formula (I) is

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (I):

each R₂ is independently selected from:

-   -   (a) -halo, —OH, —NH₂, —CN, or —NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle, -phenyl,        -naphthyl (otherwise known as -naphthalenyl), or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₈ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₅-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        -(3- to 7-membered)heterocycle, -phenyl, -naphthyl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₈ groups; or    -   (c) —CH₂CH₂OH, —(C₁-C₆)alkyl(═O)W₁, —C(O)OV₁, —C(O)N(V₁)₂, or        —S(O)₂(C₁-C₆)alkyl; or    -   (d) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkoxy, -(3- to 7-membered)heterocycle, -phenyl,        -naphthyl, and -(5- to 10-membered)heteroaryl; or    -   (e) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂NH₂, —NHC(O)W₁, —NHS(O)₂W₁, —C(O)OV₁, and        —C(O)N(V₁)₂;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each Y is independently selected from O or S;

A and B are independently selected from —H, —N(R₆)₂,—(C₃-C₁₂)cycloalkyl, or —(C₁-C₆)alkyl each of which —(C₁-C₆)alkyl isunsubstituted or substituted with —OH, —S(O)₂NH₂, or from 1 to 3independently selected -halo, or A-B together form a (C₂-C₆)bridge;

C is —H;

D is —H;

the dashed line in the piperidine or bridged piperidine central ring isabsent;

Z is a bond;

R₁ is selected from:

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that1≦(j+k)≦4;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₅ is independently selected from —(C₁-C₄)alkyl, —O(C₁-C₄)alkyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, or —C(O)OR₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl, -phenyl, or-benzyl;

each p is independently 0 or 1;

R₁₁ is selected from —H, —(C₁-C₄)alkyl, or -halo; and

each halo is independently selected from —F, —Cl, —Br, or —I.

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (I):

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂), —N(T₃)C(O)T₃,        —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 R₅ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T)₁ (T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or        —(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or        —(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2        substituents selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆,        —C(O)OT₃, —C(O)N(R₆)₂, —N(R₆)C(O)R₅ and -(5- or        6-membered)heterocycle or from 1 to 3 independently selected        -halo, or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        optionally substituted with from 1 to 3-OH or optionally        contains —HC═CH— within the (C₂-C₆)bridge, or    -   (c) A-B together form a —CH₂—N(R₆)—CH₂— bridge, a

bridge, or a

bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, RF, or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))—(3- to 7-membered)heterocycle,    -   (b) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups, or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthyl, —N(R_(c))—(C₁₄)aryl,        or —N(R_(c))—(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,—N(R₆)C(O)R₉ and -(5- or 6-membered)heterocycle or from 1 to 3independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 R₈ groups and, optionally, in which any D group carbon        atom except the carbon atom bonded directly to the piperidine or        bridged piperidine central ring, is independently replaced by O        or S; or    -   (c) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups;

Z is a bond;

R₁ is selected from:

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that1≦(j+k)≦4;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 R₈ groups and, optionally,in which any carbon atom is independently replaced by O or S, or T₁ andT₂ together can form a 5- to 8-membered ring where the number of atomsin the ring includes the nitrogen atom to which T₁ and T₂ are bonded,said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or3 R₈ groups and, optionally, any carbon atom in said 5- to 8-memberedring is independently replaced by O or S;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each p is independently 0 or 1;

R₁₁ is selected from —H or —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂;and

each halo is independently selected from —F, —Cl, —Br, or —I.

4.2 Heterocyclic-Substituted Piperidine Compounds of Formula (II)

As stated above, the invention encompasses Heterocyclic-SubstitutedPiperidine Compounds of Formula (II):

and pharmaceutically acceptable derivatives thereof where R₁, R₂, R₃, Q,Y, Z, A, B, C, D, a and the dashed line are defined above for theHeterocyclic-Substituted Piperidine Compounds of Formula (II).

In one embodiment, each Y is O.

In another embodiment, each Y is S.

In another embodiment, A is H.

In another embodiment, B is H.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups, and which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge; wherein the piperazine ring that is fused to the Q groupcan be in the endo- or exo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with an R₉ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted and which bridge optionally contains —HC═CH— within the(C₂-C₃)bridge; wherein the piperazine ring that is fused to the Q groupcan be in the endo- or exo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂)bridge, a —HC═CH— bridge,or a (C₃)bridge each of which is unsubstituted; wherein the piperazinering that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, C is H.

In another embodiment, D is H.

In another embodiment, a is 0 or 1.

In another embodiment, a is 0.

In another embodiment, a is 1.

In another embodiment, a is 2.

In another embodiment, each Y is O, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is O, A, B, C and D are each H, and a is0.

In another embodiment, each Y is S, A, B, C and D are each H, and a is0.

In another embodiment, each Y is O, A, B, C and D are each H, and a is1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, R₃ is —H, —(C₁-C₆)alkyl, —(C₁-C₆)alkylsubstituted by an R₅ group, —(C₃-C₇)cycloalkyl, or —(C₃-C₇)cycloalkylsubstituted by an R₈ group.

In another embodiment, R₃ is —H, —C(O)OV₁, —C(O)N(V₁)₂, or —(C₁-C₂)alkylsubstituted with a substituent selected from —NHS(O)₂W₁, —C(O)OV₁, and—C(O)N(V₁)₂.

In another embodiment, R₃ is —H.

In another embodiment, R₃ is —(C₁-C₆)alkyl.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by an R₈ group.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by —CN.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by an R₈ group.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by —CN.

In another embodiment, R₃ is —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is cyclopentyl, cyclohexyl, or cycloheptyl.

In another embodiment, R₃ is —H or methyl substituted by —CN.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₅ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₅ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₅ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₅ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each R₂ is independently -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, each R₂ is independently -halo.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl,cycloheptyl, or phenyl.

In another embodiment, a is 2 and each R₂ is independently -halo.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN, methyl,ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl, cycloheptyl, orphenyl.

In another embodiment, a is 1 and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1,and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 0,and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, a is 0, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 0, and R₃ is methyl, ethyl,n-propyl or iso-propyl, each of which is substituted by an R₈ group, or—H.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1, R₂is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the piperazine ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, a is 1, R₂ is -halo, optionally —F, and R₃is methyl, ethyl, n-propyl or iso-propyl, each of which is substitutedby an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein thepiperazine ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the piperazine ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, R₂ is -halo, optionally —F, andR₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, Q is naphthaleno.

In another embodiment, Q is pyridino.

In another embodiment, Z is a bond.

In another embodiment, Z is a bond and R₁ is selected from:

In another embodiment, Z is a bond, R₁ is selected from formula (i), andm is 5.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 5, and p is 0.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 5, p is 0, and R₁₁ is —H.

In another embodiment, Z is a bond, R₁ is selected from formula (i), andm is 3.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, and p is 1.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, p is 1, and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, R₁₁ is —H, p is 1, and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, Z is a bond, R₁ is selected from formula (iii),and j+k=1.

In another embodiment, Z is a bond, R₁ is selected from formula (iii),j+k=1, and p is 0.

In another embodiment, Q is pyridino, Z is a bond, and R₁ is selectedfrom:

where m is an integer selected from 3, 4 or 5;

j is an integer selected from 1 or 2;

k is 0; and

each p is an integer independently selected from 0 or 1.

In another embodiment, each p is 0.

In another embodiment, in formulas (ia) and (ib) p is 1 and R₈ isselected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3, p is 1, and R₉is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 5, p is 1, and R₈is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3 and p is 0.

In another embodiment, in formulas (ia) and (ib) m is 5 and p is 0.

In another embodiment, in formula (iii) one p is 0, the other p is 1,and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formula (iii) j is 1 and each p is 0.

In another embodiment, in formula (iii) j is 1, one p is 0, the other pis 1, and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, the Heterocyclic-Substituted Piperidine Compoundof Formula (II) is

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (II):

Q is selected from naphtho (otherwise known as naphthaleno) or pyridino;

each R₂ is independently selected from:

-   -   (a) -halo, —OH, —NH₂, —CN, or —NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle, -phenyl,        -naphthyl, or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 R₈ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₅-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        -(3- to 7-membered)heterocycle, -phenyl, -naphthyl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₈ groups; or    -   (c) —CH₂CH₂OH, —(C₁-C₆)alkyl(═O)W₁, —C(O)OV₁, —C(O)N(V₁)₂, or        —S(O)₂(C₁-C₆)alkyl; or    -   (d) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkoxy, -(3- to 7-membered)heterocycle, -phenyl,        -naphthyl, and -(5- to 10-membered)heteroaryl; or    -   (e) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂NH₂, —NHC(O)W₁, —NHS(O)₂W₁, —C(O)OV₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

A and B are independently selected from —H, —N(R₆)₂,—(C₃-C₁₂)cycloalkyl, or —(C₁-C₆)alkyl each of which —(C₁-C₆)alkyl isunsubstituted or substituted with —OH, —S(O)₂NH₂, or from 1 to 3independently selected -halo, or A-B together form a (C₂-C₆)bridge;

C is —H;

D is —H;

the dashed line in the piperidine or bridged piperidine central ring isabsent;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; or—(C₁-C₁₀)alkyl-NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₈ group; or

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₈ is independently selected from —(C₁-C₄)alkyl, —O(C₁-C₄)alkyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, or —C(O)OR₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl, -phenyl, or-benzyl;

R₁₁ is selected from —H, —(C₁-C₄)alkyl, or -halo;

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that 1≦+k)≦4;

each p is independently 0 or 1;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is 0, then R₁ is not -halo or —NO₂;

provided that when Q is pyridino, then R₂ is not imidazolyl ortriazolyl;

provided that when Q is pyridino and R₂ is -phenyl, -naphthyl, or -(5-or 6-membered)heteroaryl, then the R₂ group is not attached to apyridino atom bonded to a 5- or 6-position carbon atom; and

provided that R₃ does not include an imidazolyl group.

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (II):

Q is selected from naphthaleno or pyridino;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂), —N(T₃)C(O)T₃,        —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₉-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T₁)(T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or        —(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or        —(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2        substituents selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆,        —C(O)OT₃, —C(O)N(R₆)₂, —N(R₆)C(O)R₉ and -(5- or        6-membered)heterocycle or from 1 to 3 independently selected        -halo, or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        optionally substituted with from 1 to 3-OH or optionally        contains —HC═CH— within the (C₂-C₆)bridge, or    -   (c) A-B together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c); —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))—(3- to 7-membered)heterocycle,    -   (b) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups, or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthyl, —N(R_(c))—(C₁₄)aryl,        or —N(R_(c))—(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,—N(R₆)C(O)R₉ and -(5- or 6-membered)heterocycle or from 1 to 3independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 R₈ groups and, optionally, in which any D group carbon        atom except the carbon atom bonded directly to the piperidine or        bridged piperidine central ring, is independently replaced by O        or S; or    -   (c) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; or—(C₁-C₁₀)alkyl-NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

each R₅ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is O, R₁₁, is selected from —H or —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂;

if h is 1, R₁₁ is selected from —H, —OH, -halo, or —(C₁-C₄)alkyl whichis unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂;

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that 1≦+k)≦4;

each p is independently 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 R₈ groups and, optionally,in which any carbon atom is independently replaced by O or S, or T₁ andT₂ together can form a 5- to 8-membered ring where the number of atomsin the ring includes the nitrogen atom to which T₁ and T₂ are bonded,said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or3 R₈ groups and, optionally, any carbon atom in said 5- to 8-memberedring is independently replaced by O or S;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is 0, then R₁ is not -halo or —NO₂;

provided that when Q is pyridino, then R₂ is not imidazolyl ortriazolyl;

provided that when Q is pyridino and R₂ is -phenyl, -naphthyl, or -(5-or 6-membered)heteroaryl, then the R₂ group is not attached to apyridino atom bonded to a 5- or 6-position carbon atom; and

provided that R₃ does not include an imidazolyl group.

4.3 Heterocyclic-Substituted Piperidine Compounds of Formula (III)

As stated above, the invention encompasses Heterocyclic-SubstitutedPiperidine Compounds of Formula (III):

and pharmaceutically acceptable derivatives thereof where R₁, R₂, R₃, Q,X, Y, Z, A, B, C, D, a and the dashed line are defined above for theHeterocyclic-Substituted Piperidine Compounds of Formula (III).

In one embodiment, each Y is O.

In another embodiment, each Y is S.

In another embodiment, A is H.

In another embodiment, B is H.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups, and which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted and which bridge optionally contains —HC═CH— within the(C₂-C₃)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge.

In another embodiment, A-B together form a (C₂)bridge, a —HC═CH— bridge,or a (C₃)bridge each of which is unsubstituted; wherein the heterocyclicring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, C is H.

In another embodiment, D is H.

In another embodiment, a is 0 or 1.

In another embodiment, a is 0.

In another embodiment, a is 1.

In another embodiment, a is 2.

In another embodiment, each Y is O, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is O, A, B, C and D are each H, and a is0.

In another embodiment, each Y is S, A, B, C and D are each H, and a is0.

In another embodiment, each Y is O, A, B, C and D are each H, and a is1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, and a is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₉ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₉ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; herein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, anda is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, R₃ is —H, —(C₁-C₆)alkyl, —(C₁-C₆)alkylsubstituted by an R₈ group, —(C₃-C₇)cycloalkyl, or —(C₃-C₇)cycloalkylsubstituted by an R₈ group.

In another embodiment, R₃ is —H, —C(O)OV₁, —C(O)N(V₁)₂, or —(C₁-C₂)alkylsubstituted with a substituent selected from —NHS(O)₂W₁, —C(O)OV₁, and—C(O)N(V₁)₂.

In another embodiment, R₃ is —H.

In another embodiment, R₃ is —(C₁-C₆)alkyl.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by an R₈ group.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by —CN.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by an R₈ group.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by —CN.

In another embodiment, R₃ is —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is cyclopentyl, cyclohexyl, or cycloheptyl.

In another embodiment, R₃ is —H or methyl substituted by —CN.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₉ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₉ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each R₂ is independently -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, each R₂ is independently -halo.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl,cycloheptyl, or phenyl.

In another embodiment, a is 2 and each R₂ is independently -halo.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN, methyl,ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl, cycloheptyl, orphenyl.

In another embodiment, a is 1 and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1,and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₉ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 0,and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, a is 0, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₅ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 0, and R₃ is methyl, ethyl,n-propyl or iso-propyl, each of which is substituted by an R₈ group, or—H.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1, R₂is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₅ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the Qgroup can be in the endo- or exo-conformation with respect to the A-Bbridge, C and D are each H, a is 1, R₂ is -halo, optionally —F, and R₃is methyl, ethyl, n-propyl or iso-propyl, each of which is substitutedby an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₉ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted Or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the Q group can be in the endo- orexo-conformation with respect to the A-B bridge, C and D are each H, ais 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe Q group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, R₂ is -halo, optionally —F, andR₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, Q is benzo, naphthaleno, or (5- to10-membered)heteroaryl.

In another embodiment, Q is benzo.

In another embodiment, Q is naphthaleno.

In another embodiment, Q is pyridino, pyrimidino, pyrazino, pyridazino,pyrrolino, imidazolino, pyrazolino, triazolino, furano, oxazolino,isoxazolino, oxadiazolino, thiopheno, thiazolino, isothiazolino, orthiadiazolino.

In another embodiment, Q is pyridino.

In another embodiment, Q is benzo, naphthaleno, or pyridino.

In another embodiment, Q is benzo or pyridino.

In another embodiment, Z is a bond.

In another embodiment, Z is a bond and R₁ is selected from:

In another embodiment, Z is a bond, R₁ is selected from formula (i), andm is 5.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 5, and p is 0.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 5, p is 0, and R₁₁ is —H.

In another embodiment, Z is a bond, R₁ is selected from formula (i), andm is 3.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, and p is 1.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, p is 1, and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, R₁, is —H, p is 1, and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, Z is a bond, R₁ is selected from formula (iii),and j+k=1.

In another embodiment, Z is a bond, R₁ is selected from formula (iii),j+k=1, and p is 0.

In another embodiment, Q is benzo, Z is a bond, and R₁ is selected from:

where m is an integer selected from 3, 4 or 5;

j is an integer selected from 1 or 2;

k is 0;

each p is an integer independently selected from 0 or 1; and

and R₁₁ is —H, —C(O)OR₉, —C(O)N(R₆)₂, or —(C₁-C₄)alkyl which isunsubstituted or substituted with —C(O)OR₉ or —C(O)N(R₆)₂.

In another embodiment, Q is pyridino, Z is a bond, and R₁ is selectedfrom:

where m is an integer selected from 3, 4 or 5;

j is an integer selected from 1 or 2;

k is 0;

each p is an integer independently selected from 0 or 1; and and R₁₁ is—H, —C(O)OR₉, —C(O)N(R₆)₂, or —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —C(O)OR₉ or —C(O)N(R₆)₂.

In another embodiment, R₁₁ is —H, —C(O)OR₉ or —C(O)N(R₆)₂.

In another embodiment, R₁₁ is —H or —C(O)OR₉.

In another embodiment, R₁₁ is —H.

In another embodiment, R₁₁ is —C(O)OR₉.

In another embodiment, R₁ is —C(O)OH or —C(O)O(C₁-C₆)alkyl.

In another embodiment, R₁ is —H or —C(O)O(C₁-C₆)alkyl.

In another embodiment, R₁ is —C(O)OH or —C(O)OCH₃.

In another embodiment, R₁₁ is —H or —C(O)OCH₃.

In another embodiment, each p is 0.

In another embodiment, in formulas (ia) and (ib) p is 1 and R₈ isselected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3, p is 1, and R₈is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 5, p is 1, and R₈is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3 and p is 0.

In another embodiment, in formulas (ia) and (ib) m is 5 and p is 0.

In another embodiment, in formula (iii) one p is 0, the other p is 1,and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formula (iii) j is 1 and each p is 0.

In another embodiment, in formula (iii) j is 1, one p is 0, the other pis 1, and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, R₁₁ is —H or —C(O)O(C₁-C₆)alkyl and each p is 0.

In another embodiment, in formulas (ia) and (ib) R₁₁ is —H or—C(O)O(C₁-C₆)alkyl, p is 1, and R₈ is selected from —(C₁-C₄)alkyl,optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) R₁₁ is —H or—C(O)O(C₁-C₆)alkyl, m is 3, p is 1, and R₈ is selected from—(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) R₁₁ is —H or—C(O)O(C₁-C₆)alkyl, m is 5, p is 1, and R₈ is selected from—(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) R₁₁ is —H or—C(O)O(C₁-C₆)alkyl, m is 3, and p is 0.

In another embodiment, in formulas (ia) and (ib) R₁₁ is —H or—C(O)O(C₁-C₆)alkyl, m is 5, and p is 0.

In another embodiment, in formula (iii) R₁₁ is —H or —C(O)O(C₁-C₆)alkyl,one p is 0, the other p is 1, and R₈ is selected from —(C₁-C₄)alkyl,optionally iso-propyl.

In another embodiment, in formula (iii) R₁₁ is —H or —C(O)O(C₁-C₆)alkyl,j is 1, and each p is 0.

In another embodiment, in formula (iii) R₁₁ is —H or —C(O)O(C₁-C₆)alkyl,j is 1, one p is 0, the other p is 1, and R₈ is selected from—(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, X is —C(R₄)(R₅)— or —N(R₁₃)—.

In another embodiment, X is —C(R₄)(R₅)—.

In another embodiment, X is —CH₂—.

In another embodiment, X is —C(R₄)(R₅)—, R₄ is —(C₁-C₆)alkyl, and R₅ is—(C₁-C₆)alkyl.

In another embodiment, X is —C[(C₁-C₆)alkyl]₂—.

In another embodiment, X is —C(C₂H₅)₂—

In another embodiment, X is —N(R₁₃)—.

In another embodiment, R₁₃ is (C₁-C₄)alkyl substituted with 1, 2 or 3substituents independently selected from —(C₃-C₁₂)cycloalkyl which isunsubstituted or further substituted with 1, 2 or 3 independentlyselected R₈ groups, or -(3- to 7-membered)heterocycle which isunsubstituted or further substituted with 1, 2 or 3 independentlyselected R₈ groups.

In another embodiment, R₁₃ is —(C₁-C₄)alkyl substituted with 1, 2 or 3substituents independently selected from —OC(O)(C₃-C₈)cycloalkyl,—NHS(O)₂(C₃-C₈)cycloalkyl, —NHC(O)W₂, and —NHS(O)₂W₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl(═O)W₂ or —(C₁-C₆)alkyl-W₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl(═O)W₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl(═O)N(R₆)₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl(═O)NH(R₆).

In another embodiment, R₁₃ is —(C₁-C₆)alkyl(═O)NH(C₁-C₆)alkyl).

In another embodiment, R₁₃ is —(C₁-C₆)alkyl(═O)N[(C₁-C₆)alkyl]₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl(═O)N(CH₃)₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl-W₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl-N(R₆)₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl-NH(R₆).

In another embodiment, R₁₃ is —(C₁-C₆)alkyl-NH(C₁-C₆)alkyl).

In another embodiment, R₁₃ is —(C₁-C₆)alkyl-N[(C₁-C₆)alkyl]₂.

In another embodiment, R₁₃ is —(C₁-C₆)alkyl-N(C₂H₅)₂.

In another embodiment, X is —NH—.

In another embodiment, X is —N(C₁-C₆)alkyl where the (C₁-C₆)alkyl isoptionally substituted with 1, 2 or 3 independently selected R₈ groups.

In another embodiment, X is —N(C₁-C₄)alkyl where the (C₁-C₄)alkyl issubstituted with —N(R₆)₂.

In another embodiment, X is —N(C₂)alkyl where the (C₂)alkyl issubstituted with —N(R₆)₂.

In another embodiment, X is —N(C₁-C₄)alkyl where the (C₁-C₄)alkyl issubstituted with —C(O)N(R₉)₂.

In another embodiment, X is —N(C₁)alkyl where the (C₁)alkyl issubstituted with —C(O)N(R₉)₂.

In another embodiment, X is —N(C₁-C₄)alkyl where the (C₁-C₄)alkyl issubstituted with —C(O)OR₉.

In another embodiment, X is —N(C₁)alkyl where the (C₁)alkyl issubstituted with —C(O)OR₉.

In another embodiment, the Heterocyclic-Substituted Piperidine Compoundof Formula (III) is

In another embodiment, the Heterocyclic-Substituted Piperidine Compoundof Formula (III) is

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (III):

Q is selected from benzo, naphtho, (C₁₄)aryl, (C₃-C₁₂)cycloalkyl,(C₆-C₁₄)bicycloalkyl, (C₅-C₁₀)cycloalkenyl, (C₇-C₁₄)bicycloalkenyl, (3-to 7-membered)heterocycle, or (5- to 10-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —OH, —NH₂, —CN, or —NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle, -phenyl,        -naphthyl, or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 R₈ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₅-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        -(3- to 7-membered)heterocycle, -phenyl, -naphthyl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₈ groups; or    -   (c) —CH₂CH₂OH, —(C₁-C₆)alkyl(═O)W₁, —C(O)OV₁, —C(O)N(V₁)₂, or        —S(O)₂(C₁-C₆)alkyl; or    -   (d) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkoxy, -(3- to 7-membered)heterocycle, -phenyl,        -naphthyl, and -(5- to 10-membered)heteroaryl; or    -   (e) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂NH₂, —NHC(O)W₁, —NHS(O)₂W₁, —C(O)OV₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

X is —C(R₄)(R₅)—, —N(R₆)—, —C(R₄)(R₅)—C(R₄′)(R₅′)—, —C(R₄)(R₅)—N(R₆)—,or —N(R₆)—C(R₄)(R₅)—;

each R₄ and R₄′ is independently selected from —H, —OR₆, —(C₁-C₆)alkyl,or —(C₃-C₇)cycloalkyl; or, independently, any two of R₄ and R₅, or R₄′and R₅′, together can form an oxo group; or any two of R₄ and R₄′ canform a 4- to 8-membered cycloalkyl ring, the number of atoms in the ringincluding the atoms to which the two of R₄ and R₄′ are attached and anyintervening atoms, if present;

each R₅ and R₅′ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl;

A and B are independently selected from —H, —N(R₆)₂,—(C₃-C₁₂)cycloalkyl, or —(C₁-C₆)alkyl each of which —(C₁-C₆)alkyl isunsubstituted or substituted with —OH, —S(O)₂NH₂, or from 1 to 3independently selected -halo, or A-B together form a (C₂-C₆)bridge;

C is —H;

D is —H;

the dashed line in the piperidine or bridged piperidine central ring isabsent;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; or—(C₁-C₁₀)alkyl-NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN;    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₈ group;

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₈ is independently selected from —(C₁-C₄)alkyl, —O(C₁-C₄)alkyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, or —C(O)OR₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl, -phenyl, or-benzyl;

R₁₁ is selected from —H, —(C₁-C₄)alkyl, or -halo;

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that 1≦(+k)≦4;

each p is independently 0 or 1;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is 0, then R₁ is not -halo or —NO₂;

provided that when Q is benzo, then X is not —N(R₆)—;

provided that when Q is benzo, then R₃ is not —(C₁-C₂)alkyl substitutedwith —C(O)N(V₁)₂; and

provided that R₃ does not include an imidazolyl group.

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (III):

Q is selected from benzo, naphthaleno, (C₁₄)aryl, (C₃-C₁₂)cycloalkyl,(C₆-C₁₄)bicycloalkyl, (C₅-C₁₀)cycloalkenyl, (C₇-C₁₄)bicycloalkenyl, (3-to 7-membered)heterocycle, or (5- to 10-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂), —N(T₃)C(O)T₃,        —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

X is —C(R₄)(R₅)—, —N(R₆)—, —C(R₄)(R₅)—C(R₄′)(R₅′)—, —C(R₄)═C(R₄′)—,—C(R₄)(R₅)—N(R₆)—, or —N(R₆)—C(R₄)(R₅)—;

each R₄ and R₄′ is independently selected from —H, —OR₆, —(C₁-C₆)alkyl,or —(C₃-C₇)cycloalkyl; or, independently, any two of R₄ and R₅, or R₄′and R₅′, together can form an oxo group; or any two of R₄ and R₄′ canform a 4- to 8-membered cycloalkyl ring, the number of atoms in the ringincluding the atoms to which the two of R₄ and R₄′ are attached and anyintervening atoms, if present;

each R₅ and R₅′ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T₁)(T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or        —(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or        —(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2        substituents selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆,        —C(O)OT₃, —C(O)N(R₆)₂, —N(R₆)C(O)R₉ and -(5- or        6-membered)heterocycle or from 1 to 3 independently selected        -halo, or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        optionally substituted with from 1 to 3-OH or optionally        contains —HC═CH— within the (C₂-C₆)bridge, or    -   (c) A-B together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R)₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R)₂, R_(c), or —(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R)₂, —N(R_(c))—(C₃-C₇)cycloalkyl, or        —N(R_(c))—(3- to 7-membered)heterocycle,    -   (b) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups, or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthyl, —N(R_(c))—(C₁₄)aryl,        or —N(R_(c))—(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,—N(R₆)C(O)R₅ and -(5- or 6-membered)heterocycle or from 1 to 3independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 R₈ groups and, optionally, in which any D group carbon        atom except the carbon atom bonded directly to the piperidine or        bridged piperidine central ring, is independently replaced by O        or S; or    -   (c) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; or—(C₁-C₁₀)alkyl-NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN;    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₉-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group;

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is O, R₁₁ is selected from —H or —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂;

if h is 1, R₁₁ is selected from —H, —OH, -halo, or —(C₁-C₄)alkyl whichis unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂;

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that 1≦+k)≦4;

each p is independently 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 R₉ groups and, optionally,in which any carbon atom is independently replaced by O or S, or T₁ andT₂ together can form a 5- to 8-membered ring where the number of atomsin the ring includes the nitrogen atom to which T₁ and T₂ are bonded,said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or3 R₅ groups and, optionally, any carbon atom in said 5- to 8-memberedring is independently replaced by O or S;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is 0, then R₁ is not -halo or —NO₂;

provided that when Q is benzo, then X is not —N(R₆)—;

provided that when Q is benzo, then R₃ is not —(C₁-C₂)alkyl substitutedwith —C(O)N(V₁)₂; and

provided that R₃ does not include an imidazolyl group.

4.4 Heterocyclic-Substituted Piperidine Compounds of Formula (IV)

As stated above, the invention encompasses Heterocyclic-SubstitutedPiperidine Compounds of Formula (IV):

or a pharmaceutically acceptable derivative thereof where R₁, R₂, R₃,R₁₂, Y, Z, A, B, C, D, a and the dashed line are defined above for theHeterocyclic-Substituted Piperidine Compounds of Formula (IV).

In one embodiment, each Y is O.

In another embodiment, each Y is S.

In another embodiment, A is H.

In another embodiment, B is H.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups, and which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge; wherein the heterocyclic ring that is fused to the phenylgroup can be in the endo- or exo-conformation with respect to the A-Bbridge.

In another embodiment, A-B together form a (C₂-C₆)bridge, which isunsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge.

In another embodiment, A-B together form a (C₂-C₃)bridge, which isunsubstituted and which bridge optionally contains —HC═CH— within the(C₂-C₃)bridge; wherein the heterocyclic ring that is fused to the phenylgroup can be in the endo- or exo-conformation with respect to the A-Bbridge.

In another embodiment, A-B together form a (C₂)bridge, a —HC═CH— bridge,or a (C₃)bridge each of which is unsubstituted; wherein the heterocyclicring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge.

In another embodiment, C is H.

In another embodiment, D is H.

In another embodiment, a is 0 or 1.

In another embodiment, a is 0.

In another embodiment, a is 1.

In another embodiment, a is 2.

In another embodiment, each Y is O, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is 0or 1.

In another embodiment, each Y is O, A, B, C and D are each H, and a is0.

In another embodiment, each Y is S, A, B, C and D are each H, and a is0.

In another embodiment, each Y is O, A, B, C and D are each H, and a is1.

In another embodiment, each Y is S, A, B, C and D are each H, and a is1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0 or 1.

in another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,and a is 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0 or 1.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 0.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 1.

In another embodiment, each Y is S, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, and a is 1.

In another embodiment, R₃ is —H, —(C₁-C₆)alkyl, —(C₁-C₆)alkylsubstituted by an R₈ group, —(C₃-C₇)cycloalkyl, or —(C₃-C₇)cycloalkylsubstituted by an R₈ group.

In another embodiment, R₃ is —H, —C(O)OV₁, —C(O)N(V₁)₂, or —(C₁-C₂)alkylsubstituted with a substituent selected from —NHS(O)₂W₁, —C(O)OV₁, and—C(O)N(V₁)₂.

In another embodiment, R₃ is —H.

In another embodiment, R₃ is —(C₁-C₆)alkyl.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by an R₈ group.

In another embodiment, R₃ is —(C₁-C₆)alkyl substituted by —CN.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by an R₈ group.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachof which is substituted by —CN.

In another embodiment, R₃ is —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is cyclopentyl, cyclohexyl, or cycloheptyl.

In another embodiment, R₃ is —H or methyl substituted by —CN.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0 or 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 0.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₉ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —H,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted by an R₈ group, or—(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each Y is O, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each Y is S, A, B, C and D are each H, R₃ is —Hor methyl substituted by —CN, and a is 1.

In another embodiment, each R₂ is independently -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, each R₂ is independently -halo.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently -halo, —OH,—NH₂, —CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl,cycloheptyl, or phenyl.

In another embodiment, a is 2 and each R₂ is independently -halo.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, a is 1 and R₂ is -halo, —OH, —NH₂, —CN, methyl,ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl, cycloheptyl, orphenyl.

In another embodiment, a is 1 and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1,and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₉ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,a is 1, and R₂ is -halo, optionally —F.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, a is 1, and R₂ is -halo, optionally—F.

In another embodiment, each Y is O, A, B, C and D are each H, a is 0,and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 0, and R₃ is methyl, ethyl,n-propyl or iso-propyl, each of which is substituted by an R₈ group, or—H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,a is 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of whichis substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,a is 0, and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of whichis substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, a is 0, and R₃ is methyl, ethyl,n-propyl or iso-propyl, each of which is substituted by an R₈ group, or—H.

In another embodiment, each Y is O, A, B, C and D are each H, a is 1, R₂is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge; wherein the heterocyclic ring that is fused to thephenyl group can be in the endo- or exo-conformation with respect to theA-B bridge, C and D are each H, a is 1, R₂ is -halo, optionally —F, andR₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,a is 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═H— within the (C₂-C₃)bridge; wherein theheterocyclic ring that is fused to the phenyl group can be in the endo-or exo-conformation with respect to the A-B bridge, C and D are each H,a is 1, R₂ is -halo, optionally —F, and R₃ is methyl, ethyl, n-propyl oriso-propyl, each of which is substituted by an R₈ group, or —H.

In another embodiment, each Y is O, A-B together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge; wherein the heterocyclic ring that is fused tothe phenyl group can be in the endo- or exo-conformation with respect tothe A-B bridge, C and D are each H, a is 1, R₂ is -halo, optionally —F,and R₃ is methyl, ethyl, n-propyl or iso-propyl, each of which issubstituted by an R₈ group, or —H.

In another embodiment, R₁₂ is (C₁-C₄)alkyl substituted with 1, 2 or 3substituents independently selected from —(C₃-C₁₂)cycloalkyl which isunsubstituted or further substituted with 1, 2 or 3 independentlyselected R₉ groups, —(C₃-C₁₂)cycloalkoxy which is unsubstituted orfurther substituted with 1, 2 or 3 independently selected R₈ groups, or-(3- to 7-membered)heterocycle which is unsubstituted or furthersubstituted with 1, 2 or 3 independently selected R₈ groups.

In another embodiment, R₁₂ is —(C₁-C₄)alkyl substituted with 1, 2 or 3substituents independently selected from —OC(O)(C₃-C₈)cycloalkyl,—NHS(O)₂(C₃-C₈)cycloalkyl, —N(V₁)C(O)(C₃-C₈)cycloalkyl, —NHC(O)W₂, and—NHS(O)₂W₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)W₂ or —(C₁-C₆)alkyl-W₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)W₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)N(R₆)₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)NH(R₆).

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)NH(C₁-C₆)alkyl).

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)NH[(3- to7-membered)heterocycle].

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)N[(C₁-C₆)alkyl]₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl(═O)N(CH₃)₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl-W₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl-N(R₆)₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl-NH(R₆).

In another embodiment, R₁₂ is —(C₁-C₆)alkyl-NH(C₁-C₆)alkyl).

In another embodiment, R₁₂ is —(C₁-C₆)alkyl-N[(C₁-C₆)alkyl]₂.

In another embodiment, R₁₂ is —(C₁-C₆)alkyl-N(C₂H₅)₂.

In another embodiment, Z is a bond.

In another embodiment, Z is a bond and R₁ is selected from:

In another embodiment, Z is a bond, R₁ is selected from formula (i), andm is 5.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 5, and p is 0.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 5, p is 0, and R₁₁ is —H.

In another embodiment, Z is a bond, R₁ is selected from formula (i), andm is 3.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, and p is 1.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, p is 1, and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, Z is a bond, R₁ is selected from formula (i), mis 3, R₁₁ is —H, p is 1, and R₈ is —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, Z is a bond, R₁ is selected from formula (iii),and j+k=1.

In another embodiment, Z is a bond, R₁ is selected from formula (iii),j+k=1, and p is 0.

In another embodiment, Z is a bond and R₁ is selected from:

where m is an integer selected from 3, 4 or 5;

j is an integer selected from 1 or 2;

k is 0; and

each p is an integer independently selected from 0 or 1.

In another embodiment, each p is 0.

In another embodiment, in formulas (ia) and (ib) p is 1 and R₈ isselected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3, p is 1, and R₈is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 5, p is 1, and R₈is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formulas (ia) and (ib) m is 3 and p is 0.

In another embodiment, in formulas (ia) and (ib) m is 5 and p is 0.

In another embodiment, in formula (iii) one p is 0, the other p is 1,and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment, in formula (iii) j is 1 and each p is 0.

In another embodiment, in formula (iii) j is 1, one p is 0, the other pis 1, and R₈ is selected from —(C₁-C₄)alkyl, optionally iso-propyl.

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (IV):

each R₂ is independently selected from:

-   -   (a) -halo, —OH, —NH₂, —CN, or —NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle, -phenyl,        -naphthyl, or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 R₈ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₅-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        -(3- to 7-membered)heterocycle, -phenyl, -naphthyl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₈ groups; or    -   (c) —CH₂CH₂OH, —(C₁-C₆)alkyl(═O)W₁, —C(O)OV₁, —C(O)N(V₁)₂, or        —S(O)₂(C₁-C₆)alkyl; or    -   (d) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkoxy, -(3- to 7-membered)heterocycle, -phenyl,        -naphthyl, and -(5- to 10-membered)heteroaryl; or    -   (e) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂NH₂, —NHC(O)W₁, —NHS(O)₂W₁, —C(O)OV₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

R₁₂ is selected from:

-   -   (a) —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, —(C₁₄)aryl, -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2 or 3 R₈ groups; or    -   (b) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, -(3- to 7-membered)heterocycle, and        —(C₁₄)aryl, each of which is unsubstituted or further        substituted with 1, 2 or 3 R₈ groups; or    -   (c) —C(O)O(C₃-C₈)cycloalkyl, —CH₂CH₂OH,        —C(O)N(V₁)(C₃-C₈)cycloalkyl, or —(C₁-C₆)alkyl(═O)W₂; or    -   (d) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —OC(O)(C₃-C₈)cycloalkyl,        —NHS(O)₂(C₃-C₈)cycloalkyl, —N(V₁)C(O)(C₃-C₈)cycloalkyl,        —NHC(O)W₂, and —NHS(O)₂W₂;

each W₂ is independently selected from —(C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, and —N(R₆)₂;

A and B are independently selected from —H, —N(R₆)₂,—(C₃-C₁₂)cycloalkyl, or —(C₁-C₆)alkyl each of which —(C₁-C₆)alkyl isunsubstituted or substituted with —OH, —S(O)₂NH₂, or from 1 to 3independently selected -halo, or A-B together form a (C₂-C₆)bridge;

C is —H;

D is —H;

the dashed line in the piperidine or bridged piperidine central ring isabsent;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; or—[(C₁-C₁₀)alkyl]NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₈ group;

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₈ is independently selected from —(C₁-C₄)alkyl, —O(C₁-C₄)alkyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, or —C(O)OR₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl, -phenyl, or-benzyl;

R₁₁ is selected from —H, —(C₁-C₄)alkyl, or -halo;

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that 1≦+k)≦4;

each p is independently 0 or 1;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is O, R₁ is not -halo or —NO₂.

In another embodiment for the Heterocyclic-Substituted PiperidineCompounds of Formula (IV):

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃, —C(O)OT₃, —C(O)N(T₁)(T₂),        —S(O)₃H, —S(O)₂T₃, —S(O)₂N(T₁)(T₂), —N(T₁)(T₂), —N(T₃)C(O)T₃,        —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups;

a is an integer from 0 to 2;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, or        -(7- to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups; or    -   (d) —(C₁-C₆)alkyl(═O)W₁, —(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁,        —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, or —S(O)₂(C₁-C₆)alkyl; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₇)cycloalkyl,        —(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₉-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7-        to 10-membered)bicycloheterocycle, -phenyl, -naphthyl,        —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl; or    -   (f) —(C₁-C₃)alkyl substituted with a substituent selected from        —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁, —N(R₉)S(O)₂W₁, and        —C(O)N(V₁)₂;

each Y is independently selected from O or S;

R₁₂ is selected from:

-   -   (a) —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, each        of which is unsubstituted or substituted with 1, 2 or 3 R₈        groups; or    -   (b) —(C₁₄)aryl which is unsubstituted or substituted with 1, 2        or 3 R₇ groups; or    -   (c) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —(C₃-C₁₂)cycloalkyl which is        unsubstituted or further substituted with 1, 2 or 3 R₈ groups,        —(C₃-C₁₂)cycloalkoxy which is unsubstituted or further        substituted with 1, 2 or 3 R₈ groups, -(3- to        7-membered)heterocycle which is unsubstituted or further        substituted with 1, 2 or 3 R₈ groups, or —(C₁₄)aryl which is        unsubstituted or further substituted with 1, 2 or 3 R₇ groups;        or    -   (d) —C(O)O(C₃-C₈)cycloalkyl, —CH₂CH₂OH,        —C(O)N(V₁)(C₃-C₈)cycloalkyl, or —(C₁-C₆)alkyl(═O)W₂; or    -   (e) —(C₁-C₄)alkyl substituted with 1, 2 or 3 substituents        independently selected from —OC(O)(C₃-C₈)cycloalkyl,        —NHS(O)₂(C₃-C₈)cycloalkyl, —N(V₁) C(O)(C₃-C₈)cycloalkyl,        —NHC(O)W₂, and —NHS(O)₂W₂;

each W₂ is independently selected from —(C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, and —N(R₆)₂;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(O)OT₃, —C(O)N(T)₁ (T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or        —(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or        —(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2        substituents selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆,        —C(O)OT₃, —C(O)N(R₆)₂, —N(R₆)C(O)R₉ and -(5- or        6-membered)heterocycle or from 1 to 3 independently selected        -halo, or    -   (b) A-B together form a (C₂-C₆)bridge, which is unsubstituted or        optionally substituted with from 1 to 3-OH or optionally        contains —HC═CH— within the (C₂-C₆)bridge, or    -   (c) A-B together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))—(3- to 7-membered)heterocycle,    -   (b) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups, or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthyl, —N(R_(c))—(C₁₄)aryl,        or —N(R_(c))—(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

C is selected from —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃, —C(O)N(R₆)₂,—N(R₆)C(O)R₉ and -(5- or 6-membered)heterocycle or from 1 to 3independently selected -halo;

the dashed line in the piperidine or bridged piperidine central ringdenotes the presence or absence of a bond, and when the dashed linedenotes the presence of a bond then D is absent, otherwise D is:

-   -   (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or    -   (b) —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1,        2 or 3 R₈ groups and, optionally, in which any D group carbon        atom except the carbon atom bonded directly to the piperidine or        bridged piperidine central ring is independently replaced by O        or S; or    -   (c) -phenyl, -naphthyl, or -(5- or 6-membered)heteroaryl, each        of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; or—[(C₁-C₁₀)alkyl]NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(O)OV₁, or —C(O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group;

—Z—R₁ is 3,3-diphenylpropyl-optionally substituted at the 3 carbon ofthe propyl with —CN, —C(O)N(R₆)₂, —C(O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O or S;

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉,—S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is O, R₁₁ is selected from —H or —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂;

if h is 1, R₁₁ is selected from —H, —OH, -halo, or —(C₁-C₄)alkyl whichis unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂;

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that2≦(e+f)≦5;

j and k are independently an integer from 0 to 4 provided that 1≦+k)≦4;

each p is independently 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 R₈ groups and, optionally,in which any carbon atom is independently replaced by O or S, or T₁ andT₂ together can form a 5- to 8-membered ring where the number of atomsin the ring includes the nitrogen atom to which T₁ and T₂ are bonded,said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or3 R₈ groups and, optionally, any carbon atom in said 5- to 8-memberedring is independently replaced by O or S;

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each W₁ is independently selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, —N(R₆)₂; or    -   (b) -(5- or 6-membered)heteroaryl optionally substituted with 1,        2 or 3 independently selected —(C₁-C₆)alkyl; and

each halo is independently selected from —F, —Cl, —Br, or —I;

provided that when h is O, R₁ is not -halo or —NO₂.

4.5 Definitions

As used in connection with the Heterocyclic-Substituted PiperidineCompounds herein, the terms used herein having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Abranched alkyl means that one or more straight chain —(C₁-C₈)alkylgroups, such as methyl, ethyl or propyl, replace one or both hydrogensin a —CH₂— group of a straight chain alkyl. A branched non-cyclichydrocarbon means that one or more straight chain —(C₁-C₁₀)alkyl groups,such as methyl, ethyl or propyl, replace one or both hydrogens in a—CH₂— group of a straight chain non-cyclic hydrocarbon. Representativebranched —(C₁-C₁₀)alkyls include -iso-propyl, -sec-butyl, -iso-butyl,-tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl,1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“—(C₁-C₃)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 3 carbon atoms. Representative straightchain —(C₁-C₃)alkyls include -methyl, -ethyl, and -n-propyl.Representative branched —(C₁-C₃)alkyls include -iso-propyl.

“—(C₁-C₂)alkyl” means a straight chain non-cyclic hydrocarbon having 1or 2 carbon atoms. Representative straight chain —(C₁-C₂)alkyls include-methyl and -ethyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. A branched alkenyl means that one or morestraight chain —(C₁-C₈)alkyl groups, such as methyl, ethyl or propyl,replace one or both hydrogens in a —CH₂— or —CH═ group of a straightchain alkenyl. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl, and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl, and the like.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. A branched alkynyl means that one or morestraight chain —(C₁-C₈)alkyl groups, such as methyl, ethyl or propyl,replace one or both hydrogens in a —CH₂— group of a straight chainalkynyl. Representative straight chain and branched —(C₂-C₁₀)alkynylsinclude -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl,-2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl,-5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl,-2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl,-2-decynyl, -9-decynyl, and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl, and the like.

“—(C₁-C₆)alkoxy” means a straight chain or branched non cyclichydrocarbon having one or more ether groups and from 1 to 6 carbonatoms. Representative straight chain and branched —(C₁-C₆)alkoxysinclude methoxy, ethoxy, methoxymethyl, 2-methoxyethyl, 5-methoxypentyl,3-ethoxybutyl, and the like.

“—(C₃-C₁₂)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 12 carbon atoms. Representative (C₃-C₁₂)cycloalkyls are-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl,-cyclooctyl, -cyclononyl, -cyclodecyl, and -cyclododecyl.

“—(C₄-C₈)cycloalkyl” or “4- to 8-member cycloalkyl ring” means asaturated monocyclic hydrocarbon having from 4 to 8 carbon atoms unless,if X is —C(R₄)(R₅)—N(R₆)—C(R₄′)(R₅′)- and R₄ and R₄′ form a 4- to8-member cycloalkyl ring, the 4- to 8-member cycloalkyl ring includesthe intervening nitrogen atom (to which R₆ is attached) and the numberof atoms in the ring includes the intervening nitrogen atom.Representative —(C₄-C₈) cycloalkyls are -cyclobutyl, cyclopentyl,cyclohexyl, -cycloheptyl, and -cyclooctyl.

“—(C₃-C₈)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

“—(C₃-C₇)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 7 carbon atoms. Representative (C₃-C₇)cycloalkyls includecyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl,—and cycloheptyl.

“—(C₆-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 6 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₆-C₁₄)bicycloalkyls include -indanyl, -norbornyl,-1,2,3,4-tetrahydronaphthalenyl, -5,6,7,8-tetrahydronaphthalenyl,-perhydronaphthalenyl, and the like.

“—(C₈-C₂₀)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 20 carbon atoms and at least one saturated cyclic alkylring. Representative —(C₈-C₂₀)tricycloalkyls include -pyrenyl,-adamantyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl-aceanthrenyl, -1,2,3,4-tetrahydropenanthrenyl,-5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl,tetradecahydro-1H-cyclohepta[a]naphthalenyl,tetradecahydro-1H-cycloocta[e]indenyl,tetradecahydro-1H-cyclohepta[e]azulenyl,hexadecahydrocycloocta[b]naphthalenyl,hexadecahydrocyclohepta[a]heptalenyl, tricyclo-pentadecanyl,tricyclo-octadecanyl, tricyclo-nonadecanyl, tricyclo-icosanyl, and thelike.

“—(C₅-C₁₂)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 12 carbon atoms. Representative (C₅-C₁₂)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, -cyclododecadienyl,-norbornenyl, and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl -norbornenyl, and thelike.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -norbornenyl,and the like.

“—(C₅-C₇)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 7carbon atoms. Representative (C₅-C₇)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, and the like.

“—(C₇-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 7 to14 carbon atoms. Representative —(C₇-C₁₄)bicycloalkenyls include-bicyclo[3.2.0]hept-2-eneyl, -indenyl, -pentalenyl, -naphthalenyl,-azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl, and the like.

“—(C₈-C₂₀)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to20 carbon atoms. Representative —(C₈-C₂₀)tricycloalkenyls include-anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,as-indacenyl, s-indacenyl,2,3,6,7,8,9,10,11-octahydro-1H-cycloocta[e]indenyl,2,3,4,7,8,9,10,11-octahydro-1H-cyclohepta[a]naphthalenyl,8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalenyl,2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-cyclohepta[a]heptalenyl,1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-dicyclohepta[a,c]cyclooctenyl,2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-dibenzo[a,d]cyclononenyl, andthe like.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, a 5-membered heterocycle can contain up to4 heteroatoms, a 6-membered heterocycle can contain up to 4 heteroatoms,and a 7-membered heterocycle can contain up to 5 heteroatoms. Eachheteroatom is independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(3- to 7-membered)heterocycle can be attached via a nitrogen or carbonatom. Representative -(3- to 7-membered)heterocycles include pyridyl,furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl,thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl,dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“-(3- to 6-membered)heterocycle” or “-(3- to 6-membered)heterocyclo”means a 3- to 6-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, a 5-membered heterocycle can contain up to4 heteroatoms, and a 6-membered heterocycle can contain up to 4heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(3- to 6-membered)heterocycle can be attached via anitrogen or carbon atom. Representative -(3- to 6-membered)heterocyclesinclude pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl,2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“-(5- or 6-membered)heterocycle” or “-(5- or 6-membered)heterocyclo”means a 5- or 6-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 5-memberedheterocycle can contain up to 4 heteroatoms and a 6-membered heterocyclecan contain up to 4 heteroatoms. Each heteroatom is independentlyselected from nitrogen, which can be quaternized; oxygen; and sulfur,including sulfoxide and sulfone. The -(5- or 6-membered)heterocycle canbe attached via a nitrogen or carbon atom. Representative -(5- or6-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl,oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl,valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3- to 5-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, and a 5-membered heterocycle can contain upto 4 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The -(3- to 5-membered)heterocycle can beattached via a nitrogen or carbon atom. Representative -(3- to5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl,imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl,2,3-dihydrofuranyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolidinyl, and the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring which is either saturated, unsaturated non-aromatic,or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to4 heteroatoms independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen orcarbon atom. Representative -(7- to 10-membered)bicycloheterocyclesinclude -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl,-indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl,-purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -carbazolyl, -β-carbolinyl, -indolinyl, -isoindolinyl,-1,2,3,4-tetrahydroquinolinyl, -1,2,3,4-tetrahydroisoquinolinyl,pyrrolopyrrolyl, and the like.

“—(C₃-C₁₂)cycloalkoxy” means a saturated monocyclic hydrocarbon havingfrom 3 to 12 carbon atoms where at least one of the carbon atoms isreplaced by an oxygen atom. Representative (C₃-C₁₂)cycloalkoxy are-oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,-1,4-dioxanyl, -oxepanyl, -1,4-dioxepanyl, -oxocanyl, -1,5-dioxocanyl,-1,3,5-trioxocanyl, -oxonanyl, -1,5-dioxonanyl, -1,4,7-trioxonanyl,-oxacyclododecanyl, -1,7-dioxacyclododecanyl, and-1,5,9-trioxacyclododecanyl.

“—(C₃-C₇)cycloalkoxy” means a saturated monocyclic hydrocarbon havingfrom 3 to 7 carbon atoms where at least one of the carbon atoms isreplaced by an oxygen atom. Representative (C₃-C₇)cycloalkoxy are-oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,-1,4-dioxanyl, -oxepanyl, and -1,4-dioxepanyl.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur, orat least two carbon atoms of one or both of the rings are replaced witha heteroatom independently selected from nitrogen, oxygen, and sulfur.In one embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl,thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“-(5- or 6-membered)heteroaryl” means a monocyclic aromatic heterocyclering of 5 or 6 members where at least one carbon atom is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, one of the -(5- or 6-membered)heteroaryl's ring containsat least one carbon atom. Representative -(5- or 6-membered)heteroarylsinclude pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,5-triazinyl, and thiophenyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, —CHBrCl, —CHCl, and—CH₁₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, and —Cl₃.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

“(C₂-C₆)bridge” as used herein means a hydrocarbon chain containing 2 to6 carbon atoms joining two atoms of the piperidine ring of Formula (I),Formula (II), Formula (III), or Formula (IV) to form a fused bicyclicring system. For example, compounds of the invention can comprise a(C₂-C₆)bridge joining positions 2 and 6 of the piperidine ring (A-B cantogether form a (C₂-C₆)bridge). Examples of compounds where A-B cantogether form a (C₂-C₆)bridge include compounds comprising the followingring systems: 8-aza-bicyclo[3.2.1]octane; 9-aza-bicyclo[3.3.1]nonane;10-aza-bicyclo[4.3.1]decane; 11-aza-bicyclo[5.3.1]undecane; and12-aza-bicyclo[6.3.1]dodecane.

“Oxo”, “═O”, and the like as used herein mean an oxygen atom doublybonded to carbon or another element. “(═O)” when used in combinationwith a hydrocarbyl group having a variable number of atoms, such as—(C₁-C₆)alkyl(═O)W₁, means that two of the hydrogens of any methylenegroup are replaced by an oxo group.

“Thiooxo”, “thioxo”, “═S”, and the like as used herein mean a sulfuratom doubly bonded to carbon or another element.

“(═NH)” when used in combination with a hydrocarbyl group having avariable number of atoms, such as —(C₁-C₆)alkyl(═NH)W₁, means that twoof the hydrogens of any methylene group are replaced by an imino group.

As used herein in connection with Formula (I), when the dashed line inthe piperidine or bridged piperidine central ring is absent, thenFormula (I) is understood to appear as follows

As used herein in connection with Formula (I), when the dashed line inthe piperidine or bridged piperidine central ring indicates the presenceof a bond, then Formula (I) is understood to appear as follows

As used herein in connection with Formula (II), when the dashed line inthe piperidine or bridged piperidine central ring is absent, thenFormula (II) is understood to appear as follows

As used herein in connection with Formula (II), when the dashed line inthe piperidine or bridged piperidine central ring indicates the presenceof a bond, then Formula (II) is understood to appear as follows

As used herein in connection with Formula (III), when the dashed line inthe piperidine or bridged piperidine central ring is absent, thenFormula (III) is understood to appear as follows

As used herein in connection with Formula (III), when the dashed line inthe piperidine or bridged piperidine central ring indicates the presenceof a bond, then Formula (III) is understood to appear as follows

As used herein in connection with Formula (IV), when the dashed line inthe piperidine or bridged piperidine central ring is absent, thenFormula (IV) is understood to appear as follows

As used herein in connection with Formula (IV), when the dashed line inthe piperidine or bridged piperidine central ring indicates the presenceof a bond, then Formula (IV) is understood to appear as follows

“—[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)-” as used herein inconnection with Z means that, when h is 0, Z is a bond. When h is 1,Z—R₁, as attached to the piperidine ring bearing A and B substituents,is

where; when i is 0, the (C₁-C₁₀)alkyl is unsubstituted by an R₁ group atany position other than at the carbon atom furthest removed from thepiperidine ring bearing A and B substituents; and, when i is 1, (i.e.,the (C₁-C₁₀)alkyl is optionally substituted by R₁) the (C₁-C₁₀)alkyl issubstituted by an R₁ group at the carbon atom furthest removed from thepiperidine ring bearing A and B substituents and substituted by anotherindependently selected R₁ group at any carbon atom of the (C₁-C₁₀)alkylincluding at the carbon atom furthest removed from the piperidine ringbearing A and B substituents.

As used herein in connection with formula (i) of R₁, when the dashedline indicates the presence of a bond, then formula (i) is understood toappear as follows

As used herein in connection with formula (i) of R₁, when the dashedline is absent, then formula (I) is understood to appear as follows

The phrase “3,3-diphenylpropyl-” and the like, when used in connectionwith the —Z—R₁ group, means

where the 3 carbon of the propyl is indicated by the number 3 in thestructure above.

The phrase “tetrazolyl group” means

In one embodiment, the tetrazolyl group is

In another embodiment, the tetrazolyl group is

The phrase “quinolinyl,” “quinolinyl group” and the like means

where R₇ is defined above for the Heterocyclic-Substituted PiperidineCompounds of Formulas (I), (II) and (III) and b is zero or a positiveinteger.

The phrase “imidazolyl,” “imidazolyl group” and the like means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (II), R₇ is defined above for theHeterocyclic-Substituted Piperidine Compounds of Formulas (II) and(III), and b is zero or a positive integer. The bond(s) between animidazolyl substituent and the atom(s) of the group to which theimidazolyl substituent is attached can be effected through the removalof any hydrogen atom(s) of the imidazolyl substituent, including thehydrogen atom bonded to an imidazolyl nitrogen atom.

The phrase “triazolyl,” “triazolyl group” and the like means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (II). The bond(s) between a triazolylsubstituent and the atom(s) of the group to which the triazolylsubstituent is attached can be effected through the removal of anyhydrogen atom(s) of the triazolyl substituent, including the hydrogenatom bonded to a triazolyl nitrogen atom.

The phrase “benzo,” “benzo group” and the like, when used in connectionwith the Q group, means

where R₂, and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III).

The phrase “pyridino,” “pyridino group” and the like, when used inconnection with the Q group, means

where R₂, and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formulas (II) and (III). In one embodiment, theoptionally-substituted pyridino Q group is

In another embodiment, the optionally-substituted pyridino Q group is

In another embodiment, the optionally-substituted pyridino Q group is

In another embodiment, the optionally-substituted pyridino Q group is

The phrase “naphthaleno,” “naphthaleno group” and the like, when used inconnection with the Q group, means

where R₂, and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formulas (II) and (III) and where an R₂ groupcan be attached to any substitutable ring carbon atom of either, or bothrings, of the naphthaleno group. In one embodiment, theoptionally-substituted naphthaleno Q group is

where an R₂ group can be attached to any substitutable ring carbon atomof either, or both rings, of the naphthaleno group. In anotherembodiment, the optionally-substituted naphthaleno Q group is

where an R₂ group can be attached to any substitutable ring carbon atomof either, or both rings, of the naphthaleno group. In anotherembodiment, the optionally-substituted naphthaleno Q group is

where an R₂ group can be attached to any substitutable ring carbon atomof either, or both rings, of the naphthaleno group.

The phrase “pyrimidino”, “pyrimidino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted pyrimidino Q group is

In another embodiment, the optionally-substituted pyrimidino Q group is

The phrase “pyrazino”, “pyrazino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III).

The phrase “pyridazino”, “pyridazino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted pyridazino Q group is

In another embodiment, the optionally-substituted pyridazino Q group is

In another embodiment, the optionally-substituted pyridazino Q group is

The phrase “pyrrolino”, “pyrrolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted pyrrolino Q group is

In another embodiment, the optionally-substituted pyrrolino Q group is

In another embodiment, the optionally-substituted pyrrolino Q group is

The phrase “imidazolino”, “imidazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted imidazolino Q group is

In another embodiment, the optionally-substituted imidazolino Q group is

The phrase “pyrazolino”, “pyrazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted pyrazolino Q group is

In another embodiment, the optionally-substituted pyrazolino Q group is

In another embodiment, the optionally-substituted pyrazolino Q group is

In another embodiment, the optionally-substituted pyrazolino Q group is

The phrase “triazolino”, “triazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted triazolino Q group is

In another embodiment, the optionally-substituted triazolino Q group is

The phrase “furano”, “furano group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted furano Q group is

In another embodiment, the optionally-substituted furano Q group is

In another embodiment, the optionally-substituted furano Q group is

The phrase “oxazolino”, “oxazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted oxazolino Q group is

In another embodiment, the optionally-substituted oxazolino Q group is

The phrase “isoxazolino”, “isoxazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted isoxazolino Q group is

In another embodiment, the optionally-substituted isoxazolino Q group is

In another embodiment, the optionally-substituted isoxazolino Q group is

In another embodiment, the optionally-substituted isoxazolino Q group is

The phrase “oxadiazolino”, “oxadiazolino group” and the like, when usedin connection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted oxadiazolino Q group is

In another embodiment, the optionally-substituted oxadiazolino Q groupis

In another embodiment, the optionally-substituted oxadiazolino Q groupis

The phrase “thiopheno”, “thiopheno group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted thiopheno Q group is

In another embodiment, the optionally-substituted thiopheno Q group is

In another embodiment, the optionally-substituted thiopheno Q group is

The phrase “thiazolino”, “thiazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted thiazolino Q group is

In another embodiment, the optionally-substituted thiazolino Q group is

The phrase “isothiazolino”, “isothiazolino group” and the like, whenused in connection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted isothiazolino Q group is

In another embodiment, the optionally-substituted isothiazolino Q groupis

In another embodiment, the optionally-substituted isothiazolino Q groupis

In another embodiment, the optionally-substituted isothiazolino Q groupis

The phrase “thiadiazolino”, “thiadiazolino group” and the like, whenused in connection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Heterocyclic-SubstitutedPiperidine Compounds of Formula (III). In one embodiment, theoptionally-substituted thiadiazolino Q group is

In another embodiment, the optionally-substituted thiadiazolino Q groupis

In another embodiment, the optionally-substituted thiadiazolino Q groupis

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different.

In one embodiment, a first group is substituted with up to three secondgroups.

In another embodiment, a first group is substituted with one or twosecond groups.

In another embodiment, a first group is substituted with only one secondgroup.

The term “animal” includes, but is not limited to, a human or anon-human animal, such as a companion animal or livestock, e.g., a cow,monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit or guinea pig.

The phrase “pharmaceutically acceptable derivative,” as used herein,includes any pharmaceutically acceptable salt, solvate, prodrug,radiolabeled, stereoisomer, enantiomer, diastereomer, otherstereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,e.g., of a Heterocyclic-Substituted Piperidine Compound of theinvention. In one embodiment, the pharmaceutically acceptable derivativeis a pharmaceutically acceptable salt, solvate, radiolabeled,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of aHeterocyclic-Substituted Piperidine Compound of the invention. Inanother embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, e.g., of a Heterocyclic-SubstitutedPiperidine Compound of the invention.

The phrase “pharmaceutically acceptable salt,” as used herein, is anypharmaceutically acceptable salt that can be prepared from aHeterocyclic-Substituted Piperidine Compound including a salt formedfrom an acid and a basic functional group, such as a nitrogen group, ofa Heterocyclic-Substituted Piperidine Compound. Illustrative saltsinclude, but are not limited, to sulfate, citrate, acetate,trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a Heterocyclic-Substituted Piperidine Compound having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, cesium, and lithium; hydroxides of alkaline earthmetal such as calcium and magnesium; hydroxides of other metals, such asaluminum and zinc; ammonia and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; picoline; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-(C₁-C₃)alkyl amines),such as mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. One skilled in the art will recognize that, e.g., acid additionsalts of a Heterocyclic-Substituted Piperidine Compound can be preparedby reaction of the compounds with the appropriate acid via a variety ofknown methods.

The invention disclosed herein is also meant to encompass all solvatesof the Heterocyclic-Substituted Piperidine Compounds. “Solvates” areknown in the art and are considered to be a combination, physicalassociation and/or solvation of a Heterocyclic-Substituted PiperidineCompound with a solvent molecule, e.g., a disolvate, monosolvate orhemisolvate when the solvent molecule:Heterocyclic-SubstitutedPiperidine Compound molecule ratio is 2:1, 1:1 or 1:2, respectively.This physical association involves varying degrees of ionic and covalentbonding, including hydrogen bonding. In certain instances, the solvatecan be isolated, for example when one or more solvent molecules areincorporated into the crystal lattice of a crystalline solid. Thus,“solvate,” as used herein, encompasses both solution-phase andisolatable solvates. A Heterocyclic-Substituted Piperidine Compound ofthe invention can be present as a solvated form with a pharmaceuticallyacceptable solvent, such as water, methanol, ethanol, and the like, andit is intended that the invention include both solvated and unsolvatedHeterocyclic-Substituted Piperidine Compound forms. As “hydrate” relatesto a particular subgroup of solvates, i.e., where the solvent moleculeis water, hydrates are included within the solvates of the invention.Preparation of solvates is known in the art. For example, M. Caira etal., J. Pharmaceut. Sci., 93(3):601-611 (2004), describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparations of solvates, hemisolvate, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun., 603-604(2001). A typical, non-limiting, process involves dissolving theHeterocyclic-Substituted Piperidine Compound in a desired amount of thedesired solvent (organic, water or mixtures thereof) at temperaturesabove about 20° C. to about 25° C., cooling the solution at a ratesufficient to form crystals, and isolating the crystals by knownmethods, e.g., filtration. Analytical techniques, for example, infraredspectroscopy, can be used to show the presence of the solvent in acrystal of the solvate.

The invention disclosed herein is also meant to encompass all prodrugsof the Heterocyclic-Substituted Piperidine Compounds. “Prodrugs” areknown in the art and, while not necessarily possessing anypharmaceutical activity as such, are considered to be any covalentlybonded carrier(s) that releases the active parent drug in vivo. Ingeneral, such prodrugs will be a functional derivative of aHeterocyclic-Substituted Piperidine Compound of Formulas (I), (II),(III) and/or (IV) which is readily convertible in vivo, e.g., by beingmetabolized, into the required Heterocyclic-Substituted PiperidineCompound of Formulas (I), (II), (III) and/or (IV). Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described in, for example, Design of Prodrugs, H.Bundgaard ed., Elsevier (1985); “Drug and Enzyme Targeting, Part A,” K.Widder et al. eds., Vol. 112 in Methods in Enzymology, Academic Press(1985); Bundgaard, “Design and Application of Prodrugs,” Chapter 5 (pp.113-191) in A Textbook of Drug Design and Development, P.Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers(1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya et al.,Chem. Pharm. Bull. 32:692 (1984).

In addition, one or more hydrogen, carbon or other atoms of aHeterocyclic-Substituted Piperidine Compound can be replaced by anisotope of the hydrogen, carbon or other atoms. Such a “radiolabeled,”“radiolabeled form”, and the like of a Heterocyclic-SubstitutedPiperidine Compound, each of which is encompassed by the invention, isuseful as a research and/or diagnostic tool in metabolismpharmacokinetic studies and in binding assays. Examples of isotopes thatcan be incorporated into a Heterocyclic-Substituted Piperidine Compoundof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Radiolabeledcompounds of the invention can be prepared by methods known in the art.For example, tritiated compounds of Formula (I) can be prepared byintroducing tritium into the particular compound of Formula (I), forexample, by catalytic dehalogenation with tritium. This method caninclude reacting a suitably halogen-substituted precursor of a compoundof Formula (I) with tritium gas in the presence of a suitable catalyst,for example, Pd/C, in the presence or absence of a base. Other suitablemethods for preparing tritiated compounds can be found in Filer,Isotopes in the Physical and Biomedical Sciences, Vol. 1, LabeledCompounds (Part A), Chapter 6 (1987). ¹⁴C-labeled compounds can beprepared by employing starting materials having a ¹⁴C carbon.

A Heterocyclic-Substituted Piperidine Compound can contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The invention is also meant to encompassall such possible forms as well as their racemic and resolved forms orany mixture thereof. When a Heterocyclic-Substituted Piperidine Compoundcontains an olefinic double bond or other center of geometric asymmetry,and unless specified otherwise, it is intended to include all “geometricisomers,” e.g., both E and Z geometric isomers. All “tautomers,” e.g.,ketone-enol, amide-imidic acid, lactam-lactim, enamine-imine,amine-imine, and enamine-enimine tautomers, are intended to beencompassed by the invention as well.

As used herein, the terms “stereoisomer,” “stereoisomeric form”, and thelike are general terms for all isomers of individual molecules thatdiffer only in the orientation of their atoms in space. It includesenantiomers and isomers of compounds with more than one chiral centerthat are not mirror images of one another (“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

Optical isomers of a Heterocyclic-Substituted Piperidine Compound can beobtained by known techniques such as chiral chromatography or formationof diastereomeric salts from an optically active acid or base.

The phrase “effective amount,” when used in connection with aHeterocyclic-Substituted Piperidine Compound, means an amount effectivefor: (a) treating or preventing a Condition; (b) detectably inhibitingORL-1 receptor function in a cell; or (c) detectably activating ORL-1receptor function in a cell.

The phrase “effective amount,” when used in connection with a secondtherapeutic agent means an amount for providing the therapeutic effectof the second therapeutic agent.

The terms “modulate,” “modulating”, and the like as used herein withrespect to the ORL-1 receptor mean the mediation of a pharmacodynamicresponse (e.g., analgesia) in an animal from (i) inhibiting oractivating the receptor, or (ii) directly or indirectly affecting thenormal regulation of the receptor activity. Compounds that modulate thereceptor activity include agonists, antagonists, mixedagonists/antagonists and compounds which directly or indirectly affectregulation of the receptor activity.

The term “MeOH” means methanol, i.e., methyl alcohol.

The term “EtOH” means ethanol, i.e., ethyl alcohol.

The term “THF” means tetrahydrofuran.

The term “DMF” means N,N-dimethylformamide.

The term “DCM” means methylene chloride, i.e., dichloromethane.

The term “DCE” means dichloroethane.

The term “EtOAc” means ethyl acetate.

The term “NH₄OH” means ammonium hydroxide.

The term “TEA” means triethylamine.

The term “MeCN” means acetonitrile.

The term “NaH” means sodium hydride.

The term “AcOH” means acetic acid.

The term “DIEA” means N,N-diisopropylethylamine orN-ethyl-N-isopropylpropan-2-amine.

The term “TFFA” means trifluoroacetic anhydride or 2,2,2-trifluoroaceticanhydride.

The term “DMSO” means dimethylsulfoxide, i.e., methylsulfinylmethane.

The term “Bn” means benzyl or

The term “BOC” means tert-butyloxycarbonyl or

The term “CBZ” means benzyloxycarbonyl or

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The phrases “treatment of,” “treating”, and the like include theamelioration or cessation of a Condition or a symptom thereof. In oneembodiment, treating includes inhibiting, for example, decreasing theoverall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of,” “preventing”, and the like include theavoidance of the onset of a Condition or a symptom thereof.

4.6 Methods for Making the Heterocyclic-Substituted Piperidine Compounds

The Heterocyclic-Substituted Piperidine Compounds can be made usingconventional organic synthesis, in view of the present disclosure, andincluding the following illustrative methods shown in the schemes belowwhere A, B, Y, Z, R₁, R₂, R₃, R₁₂ and a are defined above, L is ahalogen leaving group such as Br or I, L′ is F or Cl, each R isindependently, e.g., a —(C₁-C₄)alkyl group, and q is the integer 0, 1,or 2.

In Scheme A and in the other schemes, “Lit 1” refers to the proceduresdescribed in the publications D. A. Tortolani and M. A. Poss, Org. Lett.1:1261 (1999) and/or International PCT Publication No. WO 2005/075459 A1of Euro-Celtique S. A. and “Lit 2” refers to the procedures described inU.S. Pat. No. 6,635,653 by Goehring et al.

Compounds of formula A1 and A2 are commercially available or can beprepared by methods known to the art.

A piperidinium salt of structure A1 can be reacted with a primary aminein a suitable solvent such as ethanol under reflux conditions in thepresence of a base such as potassium carbonate as described in reference“Lit 1” to provide the 1-(substituted)piperidine-4-one compound A3. Asdescribed in reference “Lit 2,” compound A3 can also be prepared byalkylation of a piperidine-4-one of structure A2 with, e.g., an alkylbromide or alkyl iodide, in a suitable solvent such as dimethylformamide, acetonitrile or dimethyl sulfoxide in the presence of aninorganic base such as potassium carbonate or an organic base such asdiisopropylethylamine. As described in reference “Lit 2,” compound A3can also be prepared by reductive amination of compound A2 with analdehyde or ketone using an acid such as acetic acid and either sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solventsuch as dichloromethane or methanol, respectively. Compound A3 can thenbe reductively aminated with a substituted or unsubstituted1,2-phenylenediamine using an acid such as acetic acid and either sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solventsuch as dichloromethane or methanol, respectively, to provide compoundA4, as described in reference “Lit 2.” Compound A4 can be dissolved in asuitable solvent such as dichloromethane and cyclized with a cyclizingreagent, such as a di-acid chloride, e.g., oxalyl dichloride or malonyldichloride (q=0 and q=1, respectively), to provide compound A5.

In Scheme B, “Lit 1b” refers to the procedures described inInternational PCT Publication No. WO 2005/075459 A1 of Euro-CeltiqueS.A.

As described in reference “Lit 1b,” compound A3 can be reacted with 50%aqueous hydroxylamine in a suitable solvent such as hexanes to providean intermediate hydroxylamine which can be converted to an oxime bydehydration in a suitable solvent such as toluene under refluxconditions using a Dean-Stark apparatus. The oxime intermediate can bereduced to the primary amine compound B1 by catalytic hydrogenationusing a catalyst such as 5% rhodium on alumina in a suitable solventsuch as ethanol under a hydrogen atmosphere at a pressure of 1 atm orgreater in a suitable apparatus such as a Parr Hydrogenator according toreference “Lit 1b.” Compound B1 can be reacted with a cyclizing reagent,such as ethyl 2-chloro-2-oxoacetate or ethyl 3-chloro-3-oxopropanoate,in the presence of a base such as triethylamine to provide compound B2.Compound B2 can be reacted with a substituted or unsubstituted2-halo-1-nitrobenzene, such as 2-fluoro-1-nitrobenzene, in the presenceof a base such as potassium carbonate in a suitable solvent such asacetonitrile under reflux conditions to provide compound B3. Compound B3can be treated with a hydrogenation catalyst such as Raney nickel in asuitable solvent such as ethanol under a hydrogen atmosphere, and theproduct immediately treated with an alkali metal alkoxide such as sodiumethoxide in a suitable solvent such as methanol or ethanol to providecompound A5.

Compound B1 can be reacted with a substituted or unsubstituted2-halo-1-nitrobenzene, such as substituted or unsubstituted2-fluoro-1-nitrobenzene, in the presence of a base as described inScheme B to provide compound C1. The reactivity of the piperidinenitrogen is then masked by reaction with a sacrificial acylating agentacetyl chloride to provide the acetyl-piperidinium salt C2. Compound C2can then be reacted with a cyclizing reagent, such as a di-acidchloride, e.g., oxalyl dichloride or malonyl dichloride, in a suitablesolvent such as dichloromethane, followed by treatment of the mixturewith ethanol to provide compound C3. As described in Scheme B, compoundC3 can then be treated with a catalyst, such as Raney nickel, under ahydrogen atmosphere to provide an intermediate which is immediatelycyclized to provide compound A5.

Compound A4 can be treated with ethoxycarbonyl isocyanate in a suitablesolvent, such as 1,2-dichloroethane, in a microwave reactor (EthosMicroSYNTH, Milestone Inc., Shelton, Conn.) to provide compound D1.

Compound A5 can be treated with sodium hydride in a suitable solvent,such as DMF, followed by treatment with an R₃ having a leaving groupsubstituent, such as an alkyl bromide, to provide compound E1.

Compound D1 can be alkylated with an R₃ group having a leaving groupsubstituent, such as an alkyl bromide, using a suitable base to providecompound F1. Compound F1 can be further alkylated with an R₁₂ grouphaving a leaving group substituent, such as an alkyl bromide, using asuitable base to provide compound F2.

Compound G1 can be hydrogenolyzed using a catalyst, such as palladium oncharcoal, in a suitable solvent, such as methanol, under a hydrogenatmosphere to provide compound G2. The —Z—R₁ group can be attached tocompound G2 as described in Scheme A, e.g., using either alkylation orreductive amination conditions, to provide compound A5.

The Compound of Formula H1 where each Y is S can be made by, e.g.,reacting a Compound of Formula A5 (i.e., where each Y is O) withLawesson's reagent (i.e.,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)according to the procedure described in “Lit 3,” which refers thepublication Perregaard et al., Bull. Soc. Chim. Belg. 86:679-691 (1977).In one embodiment, the Compound of Formula H1 can be made by reacting aCompound of Formula A5 with Lawesson's reagent in a nonpolar solventsuch as THF or toluene at a temperature of about 100° C. for about 2-3hours, as shown above.

Compound C1 can be converted to compound A4 using a catalyst, such asRaney nickel, in a suitable solvent, such as ethanol, under a hydrogenatmosphere.

Compound A5 can be reacted with epichlorohydrin in the presence of asuitable base to provide compound J1. Compound J1 can be reacted with asuitable amine, such as NH(R)₂, in a suitable solvent to providecompound J2.

The piperidine nitrogen of compound A2 can be protected as, e.g., thetrifluoroacetamide or carbobenzyloxy carbamate using trifluoroaceticanhydride or benzychloroformate, respectively, in a suitable solventsuch as dichloromethane in the presence of an organic base such astriethylamine to provide compound K1. Compound K1 can be reductivelyaminated with a substituted or unsubstituted 1,2-phenylenediamine usingsodium triacetoxyborohydride in a solvent such as dichloromethane in thepresence of acetic acid to provide compound K2. Compound K2 can becyclized with a cyclizing reagent, such as a di-acid chloride, e.g.,oxalyl dichloride or malonyl dichloride, to provide compound K3. Theprotecting group (such as —C(O)R illustrated above) can be removed understandard conditions (see, e.g., “Protective Groups in OrganicSynthesis,” T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc.,3^(rd) Ed., New York (1999), pp. 531-535, 556-557) to provide compoundK4. The —Z—R₁ group can be attached to compound K1 as described inScheme A, e.g., using either alkylation or reductive aminationconditions, to provide compound A5.

Compound L1 can be converted to compound L2 in a three step procedure asfollows. Substituted pyridine compound L1 can be treated withdi-tert-butyl-dicarbonate and 4-dimethylamino pyridine in a suitablesolvent to provide a di-BOC protected intermediate. The intermediate canbe treated with potassium carbonate to provide the mono-BOC protectedintermediate which can be converted to compound L2 by hydrogenatingusing Raney nickel or other standard conditions (using palladium oncarbon or the like). Compound L2 can be reductively aminated with asuitably functionalized 4-piperidone (containing a Z—R₁, group on thepiperidine nitrogen and substituents A and B) using sodiumtriacetoxyborohydride and an acid such as acetic acid in a suitablesolvent such as dichloromethane to provide compound L3. The BOCprotecting group can be removed under acid conditions (for example,using hydrogen chloride in ethyl acetate) to provide compound A4.

Compound A4 can be converted to the 4-methoxybenzoyl derivative compoundM1 using 4-methoxy-benzoylchloride in a suitable solvent in the presenceof an organic or inorganic base. Compound M1 can be reduced to compoundM2, e.g., using lithium aluminum hydride. As described in Scheme D,compound M2 can be converted to compound M3 using ethoxycarbonylisocyanate in a microwave reactor. Alternatively, compound A4 can bereacted with a cyclizing reagent, such as ethyl 2-chloro-2-oxoacetate orethyl 3-chloro-3-oxopropanoate, and a base such as triethylamine in asuitable solvent such as dichloromethane to provide compound M4.Compound M4 can be converted to compound A5 using an alkali metalalkoxide such as sodium ethoxide in a suitable solvent such as ethanol.

Compound N1 can be converted to compound N2 using lithiumdiisopropylamide in a suitable solvent such as tetrahydrofuran followedby treatment with a D having a leaving group substituent, e.g.,iodomethane. Compound N2 can be converted to compound N3 in a two stepprocedure. First, the ester can be hydrolyzed to the carboxylic acidusing an aqueous base such as sodium hydroxide. This can be followed bytreatment with diphenylphosphoryl azide and benzyl alcohol under Curtiusrearrangement conditions. The benzyloxycarbonyl group of compound N3 canbe removed under hydrogenolysis conditions, e.g., using palladium oncharcoal, to provide compound N4. Compound N4 can be converted tocompound N5 by reaction with a substituted or unsubstituted2-halo-1-nitrobenzene, such substituted or unsubstituted as2-fluoro-1-nitrobenzene, in the presence of a base such as potassiumcarbonate in a suitable solvent such as acetonitrile. Compound N5 can beconverted to compound N6 in a two step procedure. First, reduction ofthe nitro group can be carried out by hydrogenation using a metalcatalyst such as Raney nickel in a suitable solvent such as ethanol.This can be followed by reaction with a cyclizing reagent, such as ethyl2-chloro-2-oxoacetate or ethyl 3-chloro-3-oxopropanoate, and a base suchas triethylamine and a suitable solvent such as dichloromethane.Compound N6 can be converted to compound N7 using an alkali metalalkoxide, such as sodium ethoxide, in a suitable solvent, such asethanol, followed by removal of the protecting group R under standardconditions. The —Z—R₁, group can be attached to compound N7 as describedin Scheme A, e.g., using either alkylation or reductive aminationconditions, to provide compound N8.

Compound O1 can be reacted with a substituted or unsubstituted1,2-phenylenediamine and a catalytic amount of an acid such as aceticacid in a suitable solvent such as toluene with azeotropic water removalin a Dean-Stark apparatus to provide compound O2. Compound O2 can becyclized to compound O3 by reaction with cyclizing reagent, such as adi-acid chloride, e.g., oxalyl dichloride or malonyl dichloride, in asuitable solvent such as dichloromethane under high dilution conditions.Compound O3 can be converted to compound O4 under basic conditions in asuitable solvent, e.g., by reaction with aqueous sodium hydroxide inethanol. Alternatively, compound O3 can be alkylated with an R₃ grouphaving a leaving group substituent, such as an alkyl bromide or alkylchloride, using a suitable base such as sodium hydride in a suitablesolvent such as DMF to provide compound O5.

Compound P1 can be converted to compound P2 using the desired amineunder Buchwald-Hartwig palladium-catalyzed amination conditions, e.g.,by adapting the procedure described in the publication J. Louie and J.F. Hartwig, Tetrahedron Lett. 36(21):3609-3612 (1995).

4.7 Therapeutic Uses of the Heterocyclic-Substituted PiperidineCompounds

In accordance with the invention, the Heterocyclic-SubstitutedPiperidine Compounds are administered to an animal in need of treatmentor prevention of a Condition.

In one embodiment, an effective amount of a Heterocyclic-SubstitutedPiperidine Compound can be used to treat or prevent any conditiontreatable or preventable by inhibiting the activity of the ORL-1receptor. Examples of conditions that are treatable or preventable byinhibiting the activity of the ORL-1 receptor include, but are notlimited to, pain (CNS effect), memory disorders, obesity, constipation,depression, dementia, and Parkinsonism.

In another embodiment, an effective amount of a Heterocyclic-SubstitutedPiperidine Compound can be used to treat or prevent any conditiontreatable or preventable by activating the ORL-1 receptor. Examples ofconditions that are treatable or preventable by activating the ORL-1receptor include, but are not limited to, pain (PNS effect), anxiety,cough, diarrhea, blood pressure disorder (via vasodilation and viadiuresis), epilepsy, anorexia/cachexia, urinary incontinence, and drugabuse.

The Heterocyclic-Substituted Piperidine Compounds can be used to treator prevent acute or chronic pain. Examples of pain that can be treatedor prevented using a Heterocyclic-Substituted Piperidine Compoundinclude, but are not limited to, cancer pain, neuropathic pain, laborpain, myocardial infarction pain, pancreatic pain, colic pain,post-operative pain, headache pain, muscle pain, arthritic pain, andpain associated with a periodontal disease, including gingivitis andperiodontitis.

The Heterocyclic-Substituted Piperidine Compounds can also be used totreat or prevent pain associated with inflammation or with aninflammatory disease in an animal. Such pain can arise where there is aninflammation of the body tissue which can be a local inflammatoryresponse or a systemic inflammation. For example, aHeterocyclic-Substituted Piperidine Compound can be used to treat orprevent pain associated with inflammatory diseases including, but notlimited to, organ transplant rejection; reoxygenation injury resultingfrom organ transplantation (see Grupp et al., J. Mol, Cell Cardiol.31:297-303 (1999)) including, but not limited to, transplantation of theheart, lung, liver, or kidney; chronic inflammatory diseases of thejoints, including arthritis, rheumatoid arthritis, osteoarthritis andbone diseases associated with increased bone resorption; inflammatorybowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome,and Crohn's disease; inflammatory lung diseases, such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory diseases of the eye, including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory disease of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory disease of the skin, including sclerodermatitis,psoriasis and eczema; inflammatory diseases of the central nervoussystem, including chronic demyelinating diseases of the nervous system,multiple sclerosis, AIDS-related neurodegeneration and Alzheimer'sdisease, infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune diseases, including Type I and TypeII diabetes mellitus; diabetic complications, including, but not limitedto, diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), gangrene of thefeet, atherosclerotic coronary arterial disease, peripheral arterialdisease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, jointproblems, and a skin or mucous membrane complication (such as aninfection, a shin spot, a candidal infection or necrobiosis lipoidicadiabeticorum), immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory disease of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andatherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. AHeterocyclic-Substituted Piperidine Compound can also be used to treator prevent pain associated with inflammatory disease that can, forexample, be a systemic inflammation of the body, exemplified bygram-positive or gram negative shock, hemorrhagic or anaphylactic shock,or shock induced by cancer chemotherapy in response to pro-inflammatorycytokines, e.g., shock associated with pro-inflammatory cytokines. Suchshock can be induced, e.g., by a chemotherapeutic agent that isadministered as a treatment for cancer.

The Heterocyclic-Substituted Piperidine Compounds can also be used totreat or prevent pain associated with nerve injury (i.e., neuropathicpain). Chronic neuropathic pain is a heterogenous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. The chronic pain is differentfrom acute pain in that chronic neuropathic pain patients suffer theabnormal pain sensations that can be described as spontaneous pain,continuous superficial burning and/or deep aching pain. The pain can beevoked by heat-, cold-, and mechano-hyperalgesia, or by heat-, cold-, ormechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to, pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinalcord injury can also induce neuropathic pain. Cancer-related neuropathicpain results from tumor growth compression of adjacent nerves, brain, orspinal cord. In addition, cancer treatments, including chemotherapy andradiation therapy, can cause nerve injury. Neuropathic pain includes butis not limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The Heterocyclic-Substituted Piperidine Compounds can be used to treator prevent a migraine including, but not limited to, migraine withoutaura (“common migraine”), migraine with aura (“classic migraine”),migraine without headache, basilar migraine, familial hemiplegicmigraine, migrainous infarction, and migraine with prolonged aura.

According to the invention, some of the Heterocyclic-SubstitutedPiperidine Compounds are agonists at the ORL-1 receptor, and some of theHeterocyclic-Substituted Piperidine Compounds are antagonists at theORL-1 receptor. In another embodiment, a Heterocyclic-SubstitutedPiperidine Compound is an agonist at the ORL-1 receptor and an agonistat a μ, κ and/or δ opioid receptor, particularly at a μ opioid receptor.In another embodiment, a Heterocyclic-Substituted Piperidine Compound isan antagonist at the ORL-1 receptor and an agonist at a μ, κ and/or δopioid receptor, particularly at a μ opioid receptor. In anotherembodiment, a Heterocyclic-Substituted Piperidine Compound is an agonistat the ORL-1 receptor and an antagonist at a μ, κ and/or δ opioidreceptor, particularly at a μ opioid receptor. In another embodiment, aHeterocyclic-Substituted Piperidine Compound is an antagonist at theORL-1 receptor and an antagonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor.

The invention also provides methods for inhibiting ORL-1 receptorfunction in a cell, comprising contacting a cell capable of expressingthe ORL-1 receptor with an amount of a Heterocyclic-SubstitutedPiperidine Compound effective to inhibit ORL-1 receptor function in thecell. This method can be adapted for use in vitro as part of an assay toselect compounds that may be useful for treating or preventing aCondition in an animal. Alternatively, this method can be adapted foruse in vivo, (i.e., in an animal such as a human) by contacting a cellin the animal with an effective amount of a Heterocyclic-SubstitutedPiperidine Compound. In one embodiment, the method is useful fortreating or preventing pain in an animal in need of such treatment orprevention. In another embodiment, the method is useful for treating orpreventing a memory disorder, obesity, constipation, depression,dementia, or Parkinsonism in an animal in need of such treatment orprevention.

The invention also relates to methods for activating ORL-1 receptorfunction in a cell, comprising contacting a cell capable of expressingthe ORL-1 receptor with an amount of a Heterocyclic-SubstitutedPiperidine Compound effective to activate ORL-1 receptor function in thecell. This method can be adapted for use in vitro as part of an assay toselect compounds useful for treating or preventing, pain, anxiety,cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia,urinary incontinence, or drug abuse. Alternatively, the method can beadapted for use in vivo (i.e., in an animal such as a human), bycontacting a cell in the animal with an effective amount of aHeterocyclic-Substituted Piperidine compound. In one embodiment themethod is useful for treating or preventing pain in an animal in need ofsuch treatment or prevention. In another embodiment, the method isuseful for treating or preventing anxiety, cough, diarrhea, high bloodpressure, epilepsy, anorexia/cachexia, urinary incontinence, or drugabuse in an animal in need of such treatment or prevention.

Examples of tissue comprising cells capable of expressing the ORL-1receptor include but are not limited to brain, spinal cord, vasdeferens, and gastrointestinal tract tissue. Methods for assaying cellsthat express the ORL-1 receptor are known in the art; for example, seeY. Shimohigashi et al., “Sensitivity of opioid receptor-like receptorORL1 for chemical modification on nociceptin, a naturally occurringnociceptive peptide,” J. Biol. Chem. 271(39):23642-23645 (1996); M.Narita et al., “Identification of the G-protein coupled ORL1 receptor inthe mouse spinal cord by [³⁵S]-GTPγS binding and immunohistochemistry,”Brit. J. Pharmacol. 128:1300-1306 (1999); G. Milligan, “Principles:Extending then utility of [³⁵S]GTPγS binding assays,” TIPS 14: 87-90(2003); and S. Lazareno, “Measurement of agonist-stimulated [³⁵S]GTPγSbinding to cell membranes,” Methods in Molecular Biology 106:231-245(1999).

4.8 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the Heterocyclic-Substituted Piperidine Compoundsare advantageously useful in human and veterinary medicine. As describedabove, the Heterocyclic-Substituted Piperidine Compounds are useful fortreating or preventing a Condition in an animal in need thereof. TheHeterocyclic-Substituted Piperidine Compounds of the invention can beadministered to any animal requiring modulation of the opioid and/orORL-1 receptors.

When administered to an animal, a Heterocyclic-Substituted PiperidineCompound can be administered as a component of a composition thatcomprises a pharmaceutically acceptable carrier or excipient. Theinvention compositions, which comprise a Heterocyclic-SubstitutedPiperidine Compound, can be administered orally. AHeterocyclic-Substituted Piperidine Compound can also be administered byany other convenient route, for example, by infusion or bolus injection,by absorption through epithelial or mucocutaneous linings (e.g., oral,rectal, and intestinal mucosa, etc.) and can be administered togetherwith a second therapeutically active agent. Administration can besystemic or local. Various delivery systems are known, e.g.,encapsulation in liposomes, microparticles, microcapsules,multiparticulates, capsules, etc., and can be used to administer aHeterocyclic-Substituted Piperidine Compound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intracerebral, intravaginal,transdermal, rectal, by inhalation, or topical, particularly to theears, nose, eyes, or skin. The method of administration is left to thediscretion of the practitioner. In most instances, administration willresult in the release of a Heterocyclic-Substituted Piperidine Compoundinto the bloodstream.

In specific embodiments, it can be desirable to administer aHeterocyclic-Substituted Piperidine Compound locally. This can beachieved, for example and not by way of limitation, by local infusionduring surgery, topical application, e.g., in conjunction with a wounddressing after surgery, by injection, by means of a catheter, by meansof a suppository or enema, or by means of an implant, said implant beingof a porous, non-porous, or gelatinous material, including membranes,such as silastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce aHeterocyclic-Substituted Piperidine Compound into the central nervoussystem or gastrointestinal tract by any suitable route, includingintraventricular, intrathecal, and epidural injection, and enema.Intraventricular injection can be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, a Heterocyclic-Substituted Piperidine Compound canbe formulated as a suppository, with traditional binders and excipientssuch as triglycerides.

When a Heterocyclic-Substituted Piperidine Compound of the invention isincorporated for parenteral administration by injection (e.g.,continuous infusion or bolus injection), the formulation for parenteraladministration can be in the form of a suspension, solution, emulsion inan oily or aqueous vehicle, and such formulations can further comprisepharmaceutically necessary additives such as one or more stabilizingagents, suspending agents, dispersing agents, and the like. AHeterocyclic-Substituted Piperidine Compound of the invention can alsobe in the form of a powder for reconstitution as an injectableformulation.

In another embodiment, a Heterocyclic-Substituted Piperidine Compoundcan be delivered in a vesicle, in particular a liposome (see Langer,Science 249:1527-1533 (1990); and Treat et al., Liposomes in the Therapyof Infectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, a Heterocyclic-Substituted PiperidineCompound can be delivered in a controlled-release system orsustained-release system (see, e.g., Goodson, “Dental Applications” (pp.115-138) in Medical Applications of Controlled Release, Vol. 2,Applications and Evaluation, R. S. Langer and D. L. Wise eds., CRC Press(1984)). Other controlled- or sustained-release systems discussed in thereview by Langer, Science 249:1527-1533 (1990) can be used. In oneembodiment, a pump can be used (Langer, Science 249:1527-1533 (1990);Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al.,Surgery 88:507 (1980); and Saudek et al., N. Engl. J. Med. 321:574(1989)). In another embodiment, polymeric materials can be used (seeMedical Applications of Controlled Release (Langer and Wise eds., 1974);Controlled Drug Bioavailability, Drug Product Design and Performance(Smolen and Ball eds., 1984); Langer and Peppas, J. Macromol. Sci. Rev.Macromol. Chem. 23:61 (1983); Levy et al., Science 228:190 (1985);During et al., Ann. Neurol. 25:351 (1989); and Howard et al., J.Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled- orsustained-release system can be placed in proximity of a target of aHeterocyclic-Substituted Piperidine Compound, e.g., the spinal column,brain, or gastrointestinal tract, thus requiring only a fraction of thesystemic dose.

The invention compositions can optionally comprise a suitable amount ofa pharmaceutically acceptable excipient so as to provide the form forproper administration to the animal. Such a pharmaceutical excipient canbe a diluent, suspending agent, solubilizer, binder, disintegrant,preservative, coloring agent, lubricant, and the like. Thepharmaceutical excipient can be a liquid, such as water or an oil,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.The pharmaceutical excipient can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipient issterile when administered to an animal. Water is a particularly usefulexcipient when a Heterocyclic-Substituted Piperidine Compound isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid excipients,particularly for injectable solutions. Suitable pharmaceuticalexcipients also include starch, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene glycol, water, ethanol, and the like. The inventioncompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986).

The invention compositions can take the form of solutions, suspensions,emulsions, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule(see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the Heterocyclic-Substituted Piperidine Compounds areformulated in accordance with routine procedures as a compositionadapted for oral administration to human beings. AHeterocyclic-Substituted Piperidine Compound to be orally delivered canbe in the form of tablets, capsules, gelcaps, caplets, lozenges, aqueousor oily solutions, suspensions, granules, powders, emulsions, syrups, orelixirs, for example. When a Heterocyclic-Substituted PiperidineCompound is incorporated into oral tablets, such tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, multiply compressed or multiply layered. Techniques andcompositions for making solid oral dosage forms are described inPharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz,eds., 2nd ed.) published by Marcel Dekker, Inc. Techniques andcompositions for making tablets (compressed and molded), capsules (hardand soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences 1553-1593 (Arthur Osol, ed., 16^(th) ed., MackPublishing, Easton, Pa. 1980).

Liquid oral dosage forms include aqueous and nonaqueous solutions,emulsions, suspensions, and solutions and/or suspensions reconstitutedfrom non-effervescent granules, optionally containing one or moresuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, flavoring agents, and the like.Techniques and composition for making liquid oral dosage forms aredescribed in Pharmaceutical Dosage Forms. Disperse Systems, (Lieberman,Rieger and Banker, eds.) published by Marcel Dekker, Inc.

When a Heterocyclic-Substituted Piperidine Compound is to be injectedparenterally, it can be, e.g., in the form of an isotonic sterilesolution. Alternatively, when a Heterocyclic-Substituted PiperidineCompound is to be inhaled, it can be formulated into a dry aerosol orcan be formulated into an aqueous or partially aqueous solution.

An orally administered Heterocyclic-Substituted Piperidine Compound cancontain one or more agents, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,to provide a pharmaceutically palatable preparation. Moreover, where intablet or pill form, the compositions can be coated to delaydisintegration and absorption in the gastrointestinal tract therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compositions.In these latter platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound, which swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time-delay materialsuch as glycerol monostearate or glycerol stearate can also be used.Oral compositions can include standard excipients such as mannitol,lactose, starch, magnesium stearate, sodium saccharin, cellulose, andmagnesium carbonate. In one embodiment, the excipients are ofpharmaceutical grade.

In another embodiment, the Heterocyclic-Substituted Piperidine Compoundscan be formulated for intravenous administration. Typically,compositions for intravenous administration comprise sterile isotonicaqueous buffer. Where necessary, the compositions can also include asolubilizing agent. A Heterocyclic-Substituted Piperidine Compound forintravenous administration can optionally include a local anestheticsuch as benzocaine or prilocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherea Heterocyclic-Substituted Piperidine Compound is to be administered byinfusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where aHeterocyclic-Substituted Piperidine Compound is administered byinjection, an ampule of sterile water for injection or saline can beprovided so that the ingredients can be mixed prior to administration.

A Heterocyclic-Substituted Piperidine Compound can be administered bycontrolled-release or sustained-release means or by delivery devicesthat are known to those in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of whichis incorporated herein by reference. Such dosage forms can be used toprovide controlled- or sustained-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, multiparticulates, liposomes, microspheres, ora combination thereof to provide the desired release profile in varyingproportions. Suitable controlled- or sustained-release formulationsknown to those in the art, including those described herein, can bereadily selected for use with the active ingredients of the invention.The invention thus encompasses single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled- orsustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained-release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a Heterocyclic-Substituted Piperidine Compound to treat orprevent the Condition or a symptom thereof in a minimum amount of time.Advantages of controlled- or sustained-release compositions includeextended activity of the drug, reduced dosage frequency, and increasedcompliance. In addition, controlled- or sustained-release compositionscan favorably affect the time of onset of action or othercharacteristics, such as blood levels of the Heterocyclic-SubstitutedPiperidine Compound, and can thus reduce the occurrence of adverse sideeffects.

Controlled- or sustained-release compositions can initially release anamount of a Heterocyclic-Substituted Piperidine Compound that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release other amounts of the Heterocyclic-SubstitutedPiperidine Compound to maintain this level of therapeutic orprophylactic effect over an extended period of time. To maintain aconstant level of the Heterocyclic-Substituted Piperidine Compound inthe body, the Heterocyclic-Substituted Piperidine Compound can bereleased from the dosage form at a rate that will replace the amount ofHeterocyclic-Substituted Piperidine Compound being metabolized andexcreted from the body. Controlled- or sustained-release of an activeingredient can be stimulated by various conditions, including but notlimited to, changes in pH, changes in temperature, concentration oravailability of enzymes, concentration or availability of water, orother physiological conditions or compounds.

The amount of the Heterocyclic-Substituted Piperidine Compound that iseffective for the treatment or prevention of a condition can bedetermined by standard clinical techniques. In addition, in vitro and/orin vivo assays can optionally be employed to help identify optimaldosage ranges. The precise dose to be employed will also depend on,e.g., the route of administration and the seriousness of the Condition,and can be decided according to the judgment of a practitioner and/oreach animal's circumstances. In other examples thereof, variations willnecessarily occur depending upon the weight and physical condition(e.g., hepatic and renal function) of the animal being treated, theaffliction to be treated, the severity of the symptoms, the frequency ofthe dosage interval, the presence of any deleterious side-effects, andthe particular compound utilized, among other things.

Suitable effective dosage amounts, however, range from about 0.01 mg/kgof body weight to about 3000 mg/kg of body weight of the animal per day,although they are typically from about 0.01 mg/kg of body weight toabout 2500 mg/kg of body weight of the animal per day or from about 0.01mg/kg of body weight to about 1000 mg/kg of body weight of the animalper day. In one embodiment, the effective dosage amount is about 100mg/kg of body weight of the animal per day or less. In anotherembodiment, the effective dosage amount ranges from about 0.01 mg/kg ofbody weight to about 100 mg/kg of body weight of the animal per day of aHeterocyclic-Substituted Piperidine Compound, in another embodiment,about 0.02 mg/kg of body weight to about 50 mg/kg of body weight of theanimal per day, and in another embodiment, about 0.025 mg/kg of bodyweight to about 20 mg/kg of body weight of the animal per day.

Administration can be as a single dose or as a divided dose. In oneembodiment, an effective dosage amount is administered about every 24 huntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 h until the Condition isabated. In another embodiment, an effective dosage amount isadministered about every 8 h until the Condition is abated.

In another embodiment, an effective dosage amount is administered aboutevery 6 h until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 4 h until theCondition is abated. The effective dosage amounts described herein referto total amounts administered; that is, if more than oneHeterocyclic-Substituted Piperidine Compound is administered, theeffective dosage amounts correspond to the total amount administered.

Where a cell capable of expressing the ORL-1 receptor is contacted witha Heterocyclic-Substituted Piperidine Compound in vitro, the amounteffective for inhibiting or activating the ORL-1 receptor function in acell will typically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, inone embodiment, from about 10⁻¹² mol/L to about 10⁻⁵ mol/L, in anotherembodiment, from about 10⁻¹² mol/L to about 10⁻⁶ mol/L, and in anotherembodiment, from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of a solution orsuspension of a pharmaceutically acceptable carrier or excipient. In oneembodiment, the volume of solution or suspension comprising theHeterocyclic-Substituted Piperidine Compound will be from about 0.01 Lto about 1 mL. In another embodiment, the volume of solution orsuspension will be about 200 μL.

The Heterocyclic-Substituted Piperidine Compounds will have a bindingaffinity (K_(i)) for the human ORL-1 receptor of about 1000 nM or lessin one embodiment, or about 500 nM or less in another embodiment, about100 nM or less in another embodiment, about 50 nM or less in anotherembodiment, or about 20 nM or less in another embodiment, or about 5 nMor less in another embodiment. The binding affinity K_(i) can bemeasured in ways known to the art, e.g. by an assay utilizing membranesfrom recombinant HEK-293 cells expressing the ORL-1 receptor.

Typically, the Heterocyclic-Substituted Piperidine Compounds will have aK_(i) (nM) of from about 300 to about 0.1 for binding to ORL-1receptors. In one embodiment, the Heterocyclic-Substituted PiperidineCompounds will have a K_(i) (nM) of from about 300 to about 100. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 100 to about 35. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 35 to about 20. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 20 to about 15. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (mM) of from about 15 to about 10. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 10 to about 4. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 4 to about 1. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 1 to about 0.4. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 0.4 to about 0.1 orless.

ORL-1 GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at an ORL-1 receptor.Heterocyclic-Substituted Piperidine Compounds typically will have anORL-1 GTP EC₅₀ (nM) of from about 5000 to about 0.1 to stimulate ORL-1receptor function. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds of the invention will have an ORL-1 GTP EC₅₀ (nM)of from about 5000 to about 1000. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of from about 1000 to about 100. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have an ORL-1 GTP EC₅₀ (nM) of from about 100 to about80. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds of the invention will have an ORL-1 GTP EC₅₀ (nM) of fromabout 80 to about 50. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of from about 50 to about 35. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have an ORL-1 GTP EC₅₀ (nM) of from about 35 to about 15.In another embodiment, the Heterocyclic-Substituted Piperidine Compoundsof the invention will have an ORL-1 GTP EC₅₀ (nM) of from about 15 toabout 10. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds will have an ORL-1 GTP EC₅₀ (nM) of from about 10 to about 4.In another embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have an ORL-1 GTP EC₅₀ (nM) of from about 4 to about 1. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havean ORL-1 GTP EC₅₀ (nM) of from about 1 to about 0.4. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havean ORL-1 GTP EC₅₀ (nM) of from about 0.4 to about 0.1 or less.

ORL-1 GTP Emax (%) is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist.Typically, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have an ORL-1 GTP Emax (%) of from about 50% to about110%. In one embodiment, the Heterocyclic-Substituted PiperidineCompound Heterocyclic-Substituted Piperidine Compounds will have anORL-1 GTP Emax (%) of from about 50% to about 75%. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havean ORL-1 GTP Emax (%) of from about 75% to about 85%. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havean ORL-1 GTP Emax (%) of from about 85% to about 95%. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havean ORL-1 GTP Emax (%) of from about 95% to about 100%. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havean ORL-1 GTP Emax (%) of from about 100 to about 110% or greater.

Where a cell capable of expressing the μ-opioid receptors is contactedwith a Heterocyclic-Substituted Piperidine Compound in vitro, the amounteffective for inhibiting or activating the μ-opioid receptors functionin a cell will typically range from about 10⁻¹² mol/L to about 10⁻⁴mol/L, in one embodiment, from about 10⁻¹² mol/L to about 10⁻⁵ mol/L, inanother embodiment, from about 10⁻¹² mol/L to about 10⁻⁶ mol/L, and inanother embodiment, from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of a pharmaceutically acceptable carrier orexcipient. In one embodiment, the volume of solution or suspensioncomprising the Heterocyclic-Substituted Piperidine Compound will be fromabout 0.01 μL to about 1 mL. In another embodiment, the volume ofsolution or suspension will be about 200 μL.

The Heterocyclic-Substituted Piperidine Compounds will have a bindingaffinity (K_(i)) for the human μ-opioid receptors of about 1000 nM orless in one embodiment, or about 500 nM or less in another embodiment,about 100 nM or less in another embodiment, about 50 nM or less inanother embodiment, or about 20 nM or less in another embodiment, orabout 5 nM or less in another embodiment.

Generally, the lower the K_(i) value, the more effective theHeterocyclic-Substituted Piperidine Compounds will be at treating aCondition such as pain or diarrhea. Typically, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 3000 to about 0.1 for binding to 1-opioid receptors. In oneembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea K_(i) (nM) of from about 3000 to about 1000. In another embodiment,the Heterocyclic-Substituted Piperidine Compounds of the invention willhave a K_(i) (nM) of from about 1000 to about 650. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have a K_(i) (nM) of from about 650 to about 525. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 525 to about 250. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 250 to about 100. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 100 to about 10. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 10 to about 1. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compounds ofthe invention will have a K_(i) (nM) of from about 1 to about 0.1 orless.

μ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a μ-opioid receptor.Heterocyclic-Substituted Piperidine Compounds typically will have a pGTP EC₅₀ (nM) of from about 5000 to about 0.1 to stimulate μ-opioidreceptor function. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds of the invention will have a μ GTP EC₅₀ (mM) offrom about 5000 to about 4100. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP EC₅₀ (nM) of from about 4100 to about 3100. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have a μ GTP EC₅₀ (nM) of from about 3100 to about 2000.In another embodiment, the Heterocyclic-Substituted Piperidine Compoundsof the invention will have a μ GTP EC₅₀ (nM) of from about 2000 to about1000. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of from about1000 to about 100. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds of the invention will have a μ GTP EC₅₀ (nM) offrom about 100 to about 10. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP EC₅₀(nM) of from about 10 to about 1. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP EC₅₀(nM) of from about 1 to about 0.4. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP EC₅₀(mM) of from about 0.4 to about 0.1 or less.

μ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by DAMGO, a standard μ agonist. Generally, the ptGTP Emax (%) value measures the efficacy of a compound to treat orprevent a Condition such as pain or diarrhea. Typically, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP Emax (%) of from about 10% to about 100%. In one embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of from about 10% to about 20%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have aμ GTP Emax (%)of from about 20 to about 50%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a p GTP Emax (%)of from about 50 to about 65%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of from about 65% to about 75%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of from about 75% to about 88%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of from about 88% to about 100% or greater.

Typically, the Heterocyclic-Substituted Piperidine Compounds will have aK_(i) (nM) of from about 10,000 to about 10 for κ receptors. In oneembodiment, the Heterocyclic-Substituted Piperidine Compounds will haveno activity. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a K_(i) (nM) of from about 10,000 toabout 5000. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a K_(i) (mM) of from about 5000 to about1000. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds will have a K_(i) (nM) of from about 1000 to about 500. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a K_(i) (nM) of from about 500 to about 300. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea K_(i) (nM) of from about 300 to about 100. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 100 to about 50. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 50 to about 20. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 20 to about 15. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 15 to about 10 or less.

κ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a κ receptor.Heterocyclic-Substituted Piperidine Compounds typically will have a κGTP EC₅₀ (nM) of from about 10,000 to about 10 to stimulate κ opioidreceptor function. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (nM) of from about 10,000 toabout 5000. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (nM) of from about 5000 toabout 2000. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (nM) of from about 2000 toabout 1500. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (nM) of from about 1500 toabout 800. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (mM) of from about 800 toabout 500. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (nM) of from about 500 toabout 300. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (mM) of from about 300 toabout 100. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (nM) of from about 100 toabout 50. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds will have a κ GTP EC₅₀ (nM) of from about 50 to about 25. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a κ GTP EC₅₀ (mM) of from about 25 to about 10 or less.

κ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by U69,593. Typically, the Heterocyclic-SubstitutedPiperidine Compounds of the invention will have a κ GTP Emax (%) of fromabout 15% to about 100%. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP Emax (%) of from about 15% toabout 30%. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP Emax (%) of from about 30 toabout 40%. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP Emax (%) of from about 40 toabout 45%. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP Emax (%) of from about 45% toabout 75%. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP Emax (%) of from about 75% toabout 90%. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP Emax (%) of from about 90% toabout 100% or greater.

Typically, the Heterocyclic-Substituted Piperidine Compounds will have aK_(i) (nM) of from about 10,000 to about 10 for 6 receptors. In oneembodiment, the Heterocyclic-Substituted Piperidine Compounds will haveno activity. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a K_(i) (nM) of from about 10,000 toabout 9000. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a K_(i) (nM) of from about 9000 to about7500. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds will have a K_(i) (nM) of from about 7500 to about 6500. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a K_(i) (nM) of from about 6500 to about 5000. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea K_(i) (nM) of from about 5000 to about 3000. In another embodiment,the Heterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM)of from about 3000 to about 2500. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 2500 to about 1000. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 1000 to about 500. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 500 to about 350. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 350 to about 250. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 250 to about 100. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) offrom about 100 to about 10 or less.

δ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a δ receptor.Heterocyclic-Substituted Piperidine Compounds typically will have a 6GTP EC₅₀ (mM) of from about 10,000 to about 10 to stimulate δ opioidreceptor function. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a δ GTP EC₅₀ (nM) of from about 10,000 toabout 1000. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a δ GTP EC₅₀ (nM) of from about 1000 toabout 100. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a δ GTP EC₅₀ (nM) of from about 100 toabout 90. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds will have a δ GTP EC₅₀ (nM) of from about 90 to about 50. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a δ GTP EC₅₀ (nM) of from about 50 to about 25. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea δ GTP EC₅₀ (nM) of from about 25 to about 10 or less.

δ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by met-enkephalin. Typically, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea δ GTP Emax (%) of from about 10% to about 110%. In one embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of from about 10% to about 30%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of from about 30% to about 50%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of from about 50% to about 75%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of from about 75% to about 90%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of from about 90% to about 100%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of from about 100% to about 110% or greater.

The Heterocyclic-Substituted Piperidine Compounds can be assayed invitro or in vivo for the desired therapeutic or prophylactic activityprior to use in humans. Animal model systems can be used to demonstratesafety and efficacy.

The invention methods for treating or preventing a Condition in ananimal in need thereof can further comprise co-administering to theanimal being administered a Heterocyclic-Substituted Piperidine Compound(i.e., a first therapeutic agent) a second therapeutic agent. In oneembodiment, the second therapeutic agent is administered in an effectiveamount.

An effective amount of the second therapeutic agent will be known to theart depending on the agent. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range. In one embodiment of the invention, where asecond therapeutic agent is administered to an animal for treatment of aCondition (e.g., pain), the minimal effective amount of theHeterocyclic-Substituted Piperidine Compound will be less than itsminimal effective amount would be where the second therapeutic agent isnot administered. In this embodiment, the Heterocyclic-SubstitutedPiperidine Compound and the second therapeutic agent can actsynergistically to treat or prevent a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-II inhibitor, a 5-lipoxygenaseinhibitor, an anti-emetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca2+-channel blocker, an anti-cancer agent, an agentfor treating or preventing UI, an agent for treating or preventinganxiety, an agent for treating or preventing a memory disorder, an agentfor treating or preventing obesity, an agent for treating or preventingconstipation, an agent for treating or preventing cough, an agent fortreating or preventing diarrhea, an agent for treating or preventinghigh blood pressure, an agent for treating or preventing epilepsy, anagent for treating or preventing anorexia/cachexia, an agent fortreating or preventing drug abuse, an agent for treating or preventingan ulcer, an agent for treating or preventing IBD, an agent for treatingor preventing IBS, an agent for treating or preventing addictivedisorder, an agent for treating or preventing Parkinson's disease andparkinsonism, an agent for treating or preventing a stroke, an agent fortreating or preventing a seizure, an agent for treating or preventing apruritic condition, an agent for treating or preventing psychosis, anagent for treating or preventing Huntington's chorea, an agent fortreating or preventing ALS, an agent for treating or preventing acognitive disorder, an agent for treating or preventing a migraine, anagent for treating, preventing or inhibiting vomiting, an agent fortreating or preventing dyskinesia, an agent for treating or preventingdepression, or any mixture thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable derivatives thereof, or anymixture thereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable derivativesthereof, or any mixture thereof.

Examples of useful non-opioid analgesics include, but are not limitedto, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,a pharmaceutically acceptable derivative thereof, or any mixturethereof. Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);alkanones, including nabumetone; a pharmaceutically acceptablederivative thereof; or any mixture thereof. For a more detaileddescription of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996); and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995), which are hereby incorporated by referencein their entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, celecoxib,DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone,nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522,RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367,SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocormine,ergocominine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin,zonisamide, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful Ca2+-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, perhexyline, a pharmaceuticallyacceptable derivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, dicyclomine, a pharmaceutically acceptable derivativethereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; propanediolcarbamates, such as meprobamate and tybamate; a pharmaceuticallyacceptable derivative thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingdiarrhea include, but are not limited to, diphenoxylate, loperamide, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, γ vinyl GABA, acetazolamide,felbamate, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing drugabuse include, but are not limited to, methadone, desipramine,amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, serotoninantagonists, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of non-steroidal anti-inflammatory agents, 5-lipoxygenaseinhibitors, anti-emetics, β adrenergic blockers, antidepressants, andanti-cancer agents are known in the art and can be selected by thoseskilled in the art. Examples of useful therapeutic agents for treatingor preventing memory disorder, obesity, constipation, cough, high bloodpressure, anorexia/cachexia, an ulcer, IBD, IBS, addictive disorder,Parkinson's disease and parkinsonism, a stroke, a seizure, a pruriticcondition, psychosis, Huntington's chorea, ALS, a cognitive disorder, amigraine, dyskinesia, depression, and/or treating, preventing orinhibiting vomiting include those that are known in the art and can beselected by those skilled in the art.

A Heterocyclic-Substituted Piperidine Compound and the secondtherapeutic agent combined can act either additively or synergisticallyto treat the same condition, or they may act independently of each othersuch that the Heterocyclic-Substituted Piperidine Compound treats orprevents a first Condition and the second therapeutic agent treats orprevents a second Condition. In one embodiment, aHeterocyclic-Substituted Piperidine Compound is administeredconcurrently with a second therapeutic agent as a single compositioncomprising an effective amount of a Heterocyclic-Substituted PiperidineCompound and an effective amount of the second therapeutic agent.Alternatively, a composition comprising an effective amount of aHeterocyclic-Substituted Piperidine Compound and a second compositioncomprising an effective amount of the second therapeutic agent areconcurrently administered. In another embodiment, an effective amount ofa Heterocyclic-Substituted Piperidine Compound is administered prior orsubsequent to administration of an effective amount of the secondtherapeutic agent. In this embodiment, the Heterocyclic-SubstitutedPiperidine Compound is administered while the second therapeutic agentexerts its therapeutic effect, or the second therapeutic agent isadministered while the Heterocyclic-Substituted Piperidine Compoundexerts its therapeutic effect for treating or preventing a Condition.

A composition of the invention is prepared by a method comprisingadmixing a Heterocyclic-Substituted Piperidine Compound or apharmaceutically acceptable derivative thereof with a pharmaceuticallyacceptable carrier or excipient. Admixing can be accomplished usingmethods known for admixing a compound (or derivative) and apharmaceutically acceptable carrier or excipient. In one embodiment, theHeterocyclic-Substituted Piperidine Compound is present in thecomposition in an effective amount.

4.9 Kits

The invention further provides kits that can simplify the handling andadministration of a Heterocyclic-Substituted Piperidine Compound to ananimal.

A typical kit of the invention comprises a unit dosage form of aHeterocyclic-Substituted Piperidine Compound. In one embodiment, theunit dosage form comprises a first container, which can be sterile,containing an effective amount of a Heterocyclic-Substituted PiperidineCompound and a pharmaceutically acceptable carrier or excipient. The kitcan further comprise a label or printed instructions instructing the useof the Heterocyclic-Substituted Piperidine Compound to treat or preventa Condition. The kit can further comprise a unit dosage form of a secondtherapeutic agent, for example, a second container containing aneffective amount of the second therapeutic agent and a pharmaceuticallyacceptable carrier or excipient. In another embodiment, the kitcomprises a container containing an effective amount of aHeterocyclic-Substituted Piperidine Compound, an effective amount of asecond therapeutic agent and a pharmaceutically acceptable carrier orexcipient. Examples of second therapeutic agents include, but are notlimited to, those listed above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, that would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

The following examples illustrate various aspects of the invention, andare not to be construed to limit the claims in any manner whatsoever.

5.1 Example 1

7-Bromo-acenaphthalene (A) was prepared according to a literature methodknown to those in the art (Bachmann et al., “Synthesis of4,4-Methylenephenanthrene,” J.A.C.S. 63:204-206 (1941)). The compound offormula AB was added to 20 mL of acetonitrile. Thereafter, the mixturewas added, in one portion, to a 100 mL solution of the compound offormula AA, piperidine-4-one (1.20 g, 7.8 mmol, Sigma-Aldrich, St.Louis, Mo.), and DIEA (4.1 mL, 23.4 mmol, Sigma-Aldrich). This mixturewas heated to reflux for 48 h, cooled to about 25° C., and adsorbed ontosilica gel to provide residues that were chromatographed with a silicagel column eluted with a gradient of from 100%:0% EtOAc:MeOH to 0%:100%EtOAc:MeOH(COMBIFLASH, Teledyne Isco, Inc., Lincoln, Nebr.). The productfractions were combined and concentrated to dryness under reducedpressure to provide 1.31 g of the compound of formula AC, determined tobe about 90% pure by liquid chromatography/mass spectrometry (“LC/MS”)(yield 44.3%).

The identity of the compound of formula AC,1-(1,2-dihydroacenaphthylen-1-yl)piperidin-4-one, was confirmed using ¹HNMR and LC/MS.

Compound AC: ¹H NMR: δ_(H) (400 MHz, MeOD): 7.68 (2H, m), 7.47 (4H, m),5.04 (1H, m), 3.39 (2H, m), 2.86 (2H, m), 2.70 (2H, m), 2.45 (4H, m);LC/MS (90.1%, t_(r)=2.434 min), m/z=252.2 [M+H]⁺ (Calc: 251.3).

5.2 Example 2

1-Cyclooctylpiperidin-4-one (compound of formula BA) was purchased fromVasudha Pharma Chem LTD (Hyderabad, Andhra Pradesh, India).

The compound of formula BA (10.00 g, 48.0 mmol) and o-phenylenediamine(10.38 g, 96.0 mmol, Sigma-Aldrich) were suspended in 200 mL ofmethylene chloride. To this mixture, sodium triacetoxyborohydride(NaBH(OAc)₃, 30.42 g, 144.0 mmol, Acros Organics, Geel, Belgium) andacetic acid (10 mL) were added. These ingredients were stirred at atemperature of about 25° C. for 24 h after which the reaction mixturewas extracted 10 times with about 200 mL of water each time. The organiclayer was dried (MgSO₄), filtered, and concentrated to dryness underreduced pressure to provide 9.48 g of a compound of formula BB as alight orange oil (yield 65.6%).

The identity of the compound of formula BB,N¹-(1-cyclooctylpiperidin-4-yl)benzene-1,2-diamine, was confirmed usingLC/MS.

Compound BB: LC/MS (95%, t_(r)=1.832 min), m/z=301.1 [M+H]⁺ (Calc:302.2).

The compound of formula BB (14.40 g, 47.84 mmol) was added to 100 mL ofdry DCE. This mixture was added dropwise to a solution of malonyldichloride (10.1 g, 71.77 mmol, Sigma-Aldrich) in 200 mL of dry DCE. Theresulting mixture was magnetically stirred under an argon atmosphere ata temperature of about 25° C. for 1 h. The mixture was then warmed to60° C. for 10 h. The mixture was then cooled to a temperature of about25° C. and the solvent was removed under reduced pressure. The remainingmaterial was added to 300 mL of methanol and adsorbed onto silica gel toprovide residues that were chromatographed with a silica gel columneluted with a gradient of from 100%:0% EtOAc:MeOH to 0%:100% EtOAc:MeOH.The product fractions were combined and concentrated to dryness underreduced pressure to provide 10.0 g of Heterocyclic-SubstitutedPiperidine Compound 5 as a light orange solid (yield 58%).

The identity of Heterocyclic-Substituted Piperidine Compound 5,1-(1-cyclooctylpiperidin-4-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 5: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.43 (1H, m), 7.26 (2H, m), 7.14 (1H, m), 4.17 (1H, m), 3.37 (4H,m), 3.10-2.99 (3H, m), 2.69 (2H, m), 2.02 (2H, m), 1.87-1.46 (14H, m);LC/MS (100%, t_(r)=4.944 min), m/z=370.4 [M+H]⁺ (Calc: 369.5).

Heterocyclic-Substituted Piperidine Compound 5 (1 g) was added to 20 mLof methanol. To this was added 1 eq of 4M HCl in 1,4-dioxane. Thesolvent was removed under reduced pressure and the resulting solid wastriturated, washed with methanol, and filtered. This material was driedunder reduced pressure to provide 0.55 g of the hydrochloride ofHeterocyclic-Substituted Piperidine Compound 5 (yield 50%).

Heterocyclic-Substituted Piperidine Compound 5 (60 mg, 0.163 mmol) andK₂CO₃ (45 mg, 0.036 mmol) were added to 2 mL DMF at a temperature ofabout 25° C. To this was added methyl iodide (20 μL, 0.32 mmol, TCIAmerica, Portland, Oreg.) and the mixture was stirred for 16 h at atemperature of about 25° C. Thereafter, water was added to the mixturewhich was then extracted with EtOAc. The organic layer was washed withwater, dried (Na₂SO₄), filtered, and concentrated to dryness underreduced pressure. The residue was chromatographed with a silica gelcolumn eluted with a gradient of from 100%:0% chloroform:MeOH to 10%:90%chloroform:MeOH and the product fractions were combined and concentratedto dryness under reduced pressure. The residue was added to 1 mL ofEtOAc. To this was added 0.5 mL of 4M HCl in EtOAc. The mixture wasconcentrated to dryness under reduced pressure and the resulting solidtriturated with 10:1 EtOAc:MeOH and filtered. The residue wasconcentrated to dryness under reduced pressure to provide 9.8 mg of thehydrochloride of Heterocyclic-Substituted Piperidine Compound 29 (yield14.3%).

The identity of Heterocyclic-Substituted Piperidine Compound 29,1-(1-cyclooctylpiperidin-4-yl)-5-methyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 29: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 9.74 (1H, brs), 7.55 (2H, m), 7.41 (1H, m), 7.35 (1H, m), 4.32(1H, m), 3.41 (2H, d, J=8.0 Hz), 3.31 (3H, s), 3.15 (2H, m), 2.98 (2H,d, J=8.0 Hz), 2.63 (1H, m), 2.45 (1H, m), 2.09 (1H, m), 1.94 (2H, m),1.31-1.70 (15H, cm); LC/MS (100%, t_(r)=1.89 min), m/z=384.0 [M+H]⁺(Calc: 383).

The dihydrochloride of Heterocyclic-Substituted Piperidine Compound 30was prepared as described above except that 5-chloropyridine-2,3-diamine(B) was used in place of o-phenylenediamine. The identity ofHeterocyclic-Substituted Piperidine Compound 30,8-chloro-1-(1-cyclooctylpiperidin-4-yl)-1H-pyrido[3,2-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 30: ¹H NMR: δ_(H) (300 MHz,CD₃OD): 8.37 (1H, d, J=2.4 Hz), 8.02 (1H, d, J=2.4 Hz), 4.21 (1H, m),3.56-3.41 (4H, m), 3.19-3.13 (3H, m), 2.88-2.65 (2H, m), 2.21-1.52 (16H,m), m/z=405 [M+H]⁺ (Calc: 404.9).

The compound of formula BD was prepared as follows. A mixture of thecompound of formula BC (5-chloro-3-nitropyridin-2-amine, 1736 mg, 10mmol, Sigma-Aldrich) and 2% platinum on carbon (200 mg, Sigma-Aldrich)in methanol (20 mL) was stirred under a hydrogen atmosphere at atemperature of about 25° C. for 2 h. After filtering off the Pt/C andwashing with EtOAc, the filtrate was concentrated under reducedpressure. The resulting solid was washed with 1:1 n-hexane:diethylether, filtered, washed with n-hexane, and dried under reduced pressureat a temperature of about 25° C. to provide the compound of formula BDas a pale brown solid (yield 88%).

The identity of the compound of formula BD was confirmed using ¹H NMR.

Compound BD: ¹H NMR: δ_(H) (300 MHz, DMSO): 7.21 (1H, d, J=1.2 Hz), 6.69(1H, d, J=1.2 Hz), 5.57 (2H, m), 5.01 (2H, m).

The dihydrochloride of Heterocyclic-Substituted Piperidine Compound 31was prepared as described above except that 5-bromopyridine-2,3-diaminewas used in place of 5-chloropyridine-2,3-diamine. The identity ofHeterocyclic-Substituted Piperidine Compound 31,8-bromo-1-(1-cyclooctylpiperidin-4-yl)-1H-pyrido[3,2-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 31: ¹H NMR: δ_(H) (300 MHz,CD₃OD): 8.45 (1H, d, J=2.1 Hz), 8.12 (1H, d, J=2.1 Hz), 4.19 (1H, m),3.52-3.41 (4H, m), 3.19-3.13 (3H, m), 2.69 (2H, m), 2.20-1.48 (16H, m),m/z=450.9 [M+H]⁺ (Calc: 449.4).

5.3 Example 3

In a manner similar to Example 2, the following.Heterocyclic-Substituted Piperidine Compounds were prepared from thecompound of formula BB:

Heterocyclic-Substituted Piperidine Compound 6 was prepared by usingoxalyl dichloride (8.37 g, 66.44 mmol, Sigma-Aldrich) in place ofmalonyl dichloride. The identity of Heterocyclic-Substituted PiperidineCompound 6, 1-(1-cyclooctylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 6: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.81 (1H, m), 7.31 (3H, m), 3.57 (3H, m), 3.43 (2H, m), 3.22 (2H,m), 2.17 (4H, m), 1.99 (4H, m), 1.78-1.46 (14H, m); LC/MS (100%,t_(r)=5.011 min), m/z=356.3 [M+H]⁺ (Calc: 355.5).

Heterocyclic-Substituted Piperidine Compound 7 was prepared by using2,2-diethylmalonyl dichloride (Sigma-Aldrich) in place of malonyldichloride. The identity of Heterocyclic-Substituted Piperidine Compound7,1-(1-cyclooctylpiperidin-4-yl)-3,3-diethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 7: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.30 (2H, m), 6.99 (1H, m), 6.80 (1H, m), 3.72 (1H, m), 3.50 (3H,m), 2.41 (2H, m), 2.21 (1H, m), 2.10-1.41 (21H, m), 1.10 (6H, m); LC/MS(96.9%, t_(r)=8.655 min), m/z=426.3 [M+H]⁺ (Calc: 425.6).

5.4 Example 4

The compound of formula CA, 1-(4-isopropylcyclohexyl)piperidin-4-one,was prepared according to the procedure in S. Kolczewski et al., J. Med.Chem. 46:255 (2003).

In a manner similar to Examples 2 and 3, the followingHeterocyclic-Substituted Piperidine Compounds were prepared from thecompound of formula CA:

The identity of Heterocyclic-Substituted Piperidine Compound 9,1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 9: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.77 (1H, m), 7.29 (3H, m), 3.70 (2H, m), 3.38 (2H, m), 3.26 (3H,m), 2.21 (1H, m), 2.13-1.90 (5H, m), 1.78 (2H, m), 1.55 (3H, m), 1.24(2H, m), 0.98 (6H, m); LC/MS (100%, t_(r)=5.446 min), m/z=370.4 [M+H]⁺(Calc: 369.5).

The identity of Heterocyclic-Substituted Piperidine Compound 10,1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 10: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.57 (1H, m), 7.39 (2H, m), 7.26 (1H, m), 4.29 (1H, m), 3.59 (2H,m), 3.48 (1H, m), 3.30-3.07 (4H, m), 2.89 (2H, m), 2.17 (3H, m), 1.91(2H, m), 1.72 (1H, m), 1.51 (2H, m), 1.18 (2H, m), 0.95 (6H, m); LC/MS(100%, t_(r)=5.538 min), m/z=384.3 [M+H]⁺ (Calc: 383.5).

The identity of Heterocyclic-Substituted Piperidine Compound 11,3,3-diethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 11: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.31 (2H, m), 7.00 (1H, m), 6.81 (1H, m), 3.81-3.51 (2H, m), 3.45(1H, m), 3.28 (2H, m), 2.41 (1H, m), 2.20 (2H, s), 2.93 (7H, m), 2.78(3H, m), 2.59 (3H, m), 1.18 (8H, m), 0.99 (7H, m); LC/MS (100%,t_(r)=9.045 min), m/z=440.4 [M+H]⁺ (Calc: 439.6).

5.5 Example 5

In a manner similar to Example 3, the following Heterocyclic-SubstitutedPiperidine Compound was prepared from the compound of formula AC:

The identity of Heterocyclic-Substituted Piperidine Compound 12,1-(1-(1,2-dihydroacenaphthylen-1-yl)piperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 12: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.83 (2H, m), 7.65 (3H, m), 7.49 (1H, m), 7.38 (1H, m), 7.16 (3H,m), 6.51 (1H, m), 3.79 (2H, m), 3.57-3.31 (2H, m), 3.28-3.03 (6H, m),1.91 (2H, m); LC/MS (100%, t_(r)=5.009 min), m/z=356.3 [M+H]⁺ (Calc:355.5).

5.6 Example 6

The compound of formula BA was converted to the compound of formula DA,4-amino-N-cyclooctylpiperidine, by procedures known to those in the art,e.g., as described in International PCT Publication No. WO 2005/075459A1 of Euro-Celtique S.A. published Aug. 18, 2005.

The compound of formula DA (2.00 g, 9.52 mmol) was dissolved in 25 mL ofmethanol and charged into a 100 mL high pressure microwave reactionvessel (MicroSYNTH Model HTR-300/6 S, Milestone Inc., Shelton, Conn.).To this was added 2,4-difluoro-1-nitrobenzene (1.43 g, 9.52 mmol). Thevessel was sealed, placed into a microwave reactor (MicroSYNTH), warmed,with stirring, to 100° C., and maintained at that temperature for 1 h.The reaction mixture was cooled to a temperature of about 25° C.,concentrated onto silica to provide residues that were chromatographedwith a silica gel column eluted with a gradient of from 100%:0%EtOAc:MeOH to 50%:50% EtOAc:MeOH. The product fractions were combinedand concentrated to dryness under reduced pressure to provide 1.57 g ofthe compound of formula DB as a bright orange solid.

The identity of the compound of formula DB,1-cyclooctyl-N-(5-fluoro-2-nitrophenyl)piperidin-4-amine, was confirmedusing ¹H NMR and LC/MS.

Compound DB: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 8.21 (2H, m), 6.48 (1H, m),6.32 (1H, m), 4.41 (1H, m), 2.80 (2H, m), 2.63 (1H, m), 2.40 (2H, m),2.06 (2H, m), 2.38-2.82 (16H, m); LC/MS (100%, t_(r)=2.456 min),m/z=350.2 [M+H]⁺ (Calc: 349.4).

The compound of formula DB was added to 100 mL of methanol and 1 g ofRaney nickel (Alfa Aesar, Ward Hill, Mass.) was added. In a sealedvessel, the mixture was stirred under an atmosphere of hydrogen (5 atm)for 18 h. The Raney nickel was filtered off and the mixture concentratedto dryness to provide the compound of formula DC,N¹-(1-cyclooctylpiperidin-4-yl)-5-fluorobenzene-1,2-diamine, which LC/MSshowed to be >99% pure material.

Thereafter, in a manner similar to Example 2, Heterocyclic-SubstitutedPiperidine Compound 16 was prepared from the compound of formula DC.

The identity of Heterocyclic-Substituted Piperidine Compound 16,1-(1-cyclooctylpiperidin-4-yl)-8-fluoro-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 16: ¹H NMR: δ_(H) (400 MHz,CD₃OD) 7.35 (1 h, d, J=15 Hz), 7.23 (1H, m), 7.15 (1H, m), 4.30 (1H, m),3.45 (4H, m), 3.30 (1H, d, J=15 Hz), 3.20 (2H, t, J=10 Hz), 3.10 (1H, d,J=15 Hz), 2.80 (2H, m), 2.10 (2H, m), 1.95 (2H, m), 1.90-1.50 (12H, m);LC/MS, m/z=388.2 [M+H]⁺.

Heterocyclic-Substituted Piperidine Compound 32 was prepared from thecompound of formula DA as described above except that3-fluoro-4-nitrophenyl-4-methylbenzenesulfonate (F) was used in place of2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 32,1-(1-cyclooctylpiperidin-4-yl)-8-tosyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 32: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.08 (1H, m), 7.01 (2H, m), 4.43 (1H, m), 3.91 (3H, s), 3.45 (4H,m), 3.05-3.29 (3H, m), 2.71 (2H, m), 2.18 (1H, m), 2.00 (3H, m),1.51-1.89 (12H, m); LC/MS (100%, t_(r)=5.139 min), m/z=400.4 [M+H]⁺(Calc: 399.5).

Heterocyclic-Substituted Piperidine Compound 33 was prepared as follows.Heterocyclic-Substituted Piperidine Compound 32 (280 mg, 0.7 mmol) wasadded to dry ethanol (10 mL). To this, potassium hydroxide (1.4 g, 25mmol) in 10 mL of water was added. The reaction mixture was warmed toreflux for 18 h. Thereafter, the mixture was adsorbed onto silica gel toprovide residues that were chromatographed with a silica gel columneluted with a gradient of from 100%:0% EtOAc:MeOH to 0%:100%EtOAc:MeOH(COMBIFLASH). The product fractions were combined andconcentrated to dryness under reduced pressure to provideHeterocyclic-Substituted Piperidine Compound 33.

The identity of Heterocyclic-Substituted Piperidine Compound 33,1-(1-cyclooctylpiperidin-4-yl)-8-hydroxy-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 33: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.19 (1H, m), 6.89 (1H, m), 6.79 (1H, m), 4.25 (1H, m), 3.48 (1H,m), 3.27 (1H, m), 3.05 (3H, m), 2.60 (2H, m), 2.11 (1H, m), 1.90 (5H,m), 1.41-1.81 (11H, m); LC/MS (100%, t_(r)=4.809 min), m/z=386.2 [M+H]⁺(Calc: 385.5).

The compound of formula DF,3-fluoro-4-nitrophenyl-4-methylbenzenesulfonate, was prepared asfollows.

3-Fluoro-4-nitrophenol (DD, 5 g, 31.83 mmol, Sigma-Aldrich) was added to100 mL dry acetone. To this, 4-methylbenzene-1-sulfonyl chloride (E,7.28 g, 38.19 mmol, Sigma-Aldrich) and potassium carbonate (11.0 g,79.57 mmol) were added. In a sealed vessel, the reaction mixture waswarmed to reflux for 2 h. The reaction mixture was cooled to atemperature of about 25° C. and concentrated to dryness under reducedpressure. The residue was partitioned between ethyl acetate (200 mL) andwater (200 mL). The organic portion was separated, dried (MgSO₄),filtered, and concentrated to dryness under reduced pressure to providethe compound of formula DF.

5.7 Example 7

In a manner similar to Example 6, the following Heterocyclic-SubstitutedPiperidine Compound was prepared from the compound of formula DA exceptthat 4-methyl-2-fluoro-1-nitrobenzene was used in place of2,4-difluoro-1-nitrobenzene:

The identity of Heterocyclic-Substituted Piperidine Compound 34,1-(1-cyclooctylpiperidin-4-yl)-8-methyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 34: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.23 (1H, m), 7.09 (1H, m), 7.01 (1H, m), 4.19 (1H, m), 4.38 (4H,m), 3.12 (2H, m), 2.98 (1H, m), 2.68 (2H, m), 2.33 (3H, s), 1.97 (4H,m), 1.72 (4H, m), 1.32-1.65 (10H, m); LC/MS (97.4%, t_(r)=5.258 min),m/z 384.3 [M+H]⁺ (Calc: 383.5).

In a manner similar to Examples 3 and 6, the followingHeterocyclic-Substituted Piperidine Compounds were prepared from thecompound of formula DA:

The identity of Heterocyclic-Substituted Piperidine Compound 17,1-(1-cyclooctylpiperidin-4-yl)-7-fluoroquinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 17: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.61 (1H, d), 7.22 (1H, t), 6.98 (1H, m), 4.74 (1H, m), 3.53 (3H,m), 3.38 (2H, m), 3.19 (2H, m), 2.09 (4H, m), 1.90 (4H, m), 1.80-1.49(8H, m); LC/MS (97.3%, t_(r)=7.689 min), m/z=374.2 [M+H]⁺ (Calc.:373.5).

Heterocyclic-Substituted Piperidine Compound 18 was prepared from thecompound of formula DA except that 2,6-difluoro-1-nitrobenzene was usedin Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 18,1-(1-cyclooctylpiperidin-4-yl)-5-fluoroquinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 18: OH (400 MHz, MeOD):7.57 (1H, m), 7.28 (1H, m), 7.11 (1H, m), 4.86 (1H, m), 3.58 (3H, m),3.41 (2H, m), 3.20 (2H, m), 2.10 (4H, m), 1.90 (4H, m), 1.80-1.49 (8H,m); LC/MS (100%, t_(r)=4.862 min), m/z=374.2 [M+H]⁺ (Calc.: 373.5).

Heterocyclic-Substituted Piperidine Compound 35 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and2-fluoro-5-(trifluoromethyl)-1-nitrobenzene was used in Example 6 inplace of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 35,1-(1-cyclooctylpiperidin-4-yl)-6-(trifluoromethyl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 35: δ_(H) (400 MHz, MeOD):7.91 (1H, m), 7.58 (1H, m), 7.51 (1H, s), 4.22 (3H, q), 3.55 (3H, m),3.39 (2H, m), 3.18 (2H, m), 2.09 (4H, m), 1.87 (4H, m), 1.48-1.81 (8H,m), 1.32 (4H, t); LC/MS (100%, t_(r)=5.705 min), m/z=424.2 [M+H]⁺ (Calc:423.5).

Heterocyclic-Substituted Piperidine Compound 36 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and 1-(4-fluoro-3-nitrophenyl)ethanone wasused in Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 36,6-acetyl-1-(1-cyclooctylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 36: δ_(H) (400 MHz, MeOD):7.91 (1H, m), 7.82 (2H, m), 4.22 (1H, q), 3.44 (2H, m), 3.17 (4H, m),2.64 (3H, s), 2.02 (4H, m), 1.50-1.98 (14H, m), 1.32 (1H, t); LC/MS(97.1%, t_(r)=4.841 min), m/z=398.3 [M+H]⁺ (Calc: 397.5).

Heterocyclic-Substituted Piperidine Compound 37 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and 2,3-difluoro-1-nitrobenzene was used inExample 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 37,1-(1-cyclooctylpiperidin-4-yl)-8-fluoroquinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 37: δ_(H) (400 MHz, MeOD):7.23 (1H, m), 7.08 (2H, m), 4.66 (1H, m), 4.22 (2H, q), 3.57 (2H, m),3.54 (1H, m), 3.28 (2H, m), 3.19 (2H, m), 2.20 (2H, m), 2.02 (2H, m),1.89 (4H, m), 1.45-1.79 (8H, m), 1.32 (31, t); LC/MS (100%, t_(r)=5.109min), m/z=374.2 [M+H]⁺ (Calc: 373.5).

Heterocyclic-Substituted Piperidine Compound 38 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and2-fluoro-5-(methylsulfonyl)-1-nitrobenzene was used in Example 6 inplace of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound381-(1-cyclooctylpiperidin-4-yl)-6-(methylsulfonyl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 38: δ_(H) (400 MHz,DMSO-d₆): 7.92 (1H, m), 7.81 (2H, m), 4.22 (1H, q), 3.67 (2H, m), 3.51(1H, m), 3.40 (2H, m), 3.18 (5H, m), 2.11 (4H, m), 1.91 (4H, m),1.51-1.79 (8H, m), 1.32 (2H, t); LC/MS (97.0%, t_(r)=4.730 min),m/z=434.2 [M+H]⁺ (Calc: 433.6).

Heterocyclic-Substituted Piperidine Compound 39 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and 6-chloro-2-fluoro-1-nitrobenzene was usedin Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 39,5-chloro-1-(1-cyclooctylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 39: δ_(H) (400 MHz, MeOD):7.70 (1H, m), 7.39 (1H, m), 7.30 (1H, m), 4.22 (4H, q), 3.78 (2H, m),3.56 (3H, m), 3.21 (2H, m), 2.10 (4H, m), 1.90 (4H, m), 1.48-1.79 (8H,m), 1.34 (6H, t); LC/MS (100%, t_(r)=5.258 min), m/z=390.1 [M+H]⁺ (Calc:389.9).

Heterocyclic-Substituted Piperidine Compound 40 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and 5-chloro-2-fluoro-1-nitrobenzene was usedin Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 40,6-chloro-1-(1-cyclooctylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 40: δ_(H) (400 MHz, MeOD):7.68 (1H, m), 7.29 (2H, m), 4.78 (1H, m), 4.22 (2H, q), 3.58 (3H, m),3.40 (2H, m), 3.18 (2H, m), 2.09 (4H, m), 1.90 (4H, m), 1.47-1.79 (8H,m), 1.34 (3H, t); LC/MS (97.1%, t_(r)=5.356 min), m/z=390.1 [M+H]⁺(Calc: 389.9).

Heterocyclic-Substituted Piperidine Compound 41 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and 4-methyl-2-fluoro-1-nitrobenzene was usedin Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 41,1-(1-cyclooctylpiperidin-4-yl)-7-methylquinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 41: δ_(H) (400 MHz, MeOD):7.59 (1H, s), 7.14 (2H, m), 4.88 (1H, m), 3.59 (4H, m), 3.47 (2H, m),3.23 (2H, m), 2.49 (3H, s), 2.09 (4H, m), 1.92 (4H, m), 1.47-1.82 (8H,m); LC/MS (100%, t_(r)=5.347 min), m/z=370.4 [M+H]⁺ (Calc: 369.5).

Heterocyclic-Substituted Piperidine Compound 42 was prepared from thecompound of formula DA except that oxalic acid was used in Example 3 inplace of oxalyl dichloride and methyl 4-fluoro-3-nitrobenzoate was usedin Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 42, methyl1-(1-cyclooctylpiperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 42: δ_(H) (400 MHz, MeOD):7.91 (2H, m), 7.82 (1H, m), 4.78 (1H, m), 4.22 (1H, q), 3.95 (3H, s),3.50 (3H, m), 3.18 (2H, m), 2.09 (4H, m), 1.90 (4H, m), 1.48-1.81 (8H,m), 1.34 (1H, t); LC/MS (97.0%, t_(r)=5.085 min), m/z=414.3 [M+H]⁺(Calc: 413.5).

5.8 Example 8

In a manner similar to Examples 2 and 6, the followingHeterocyclic-Substituted Piperidine Compounds were prepared from thecompound of formula DA:

Heterocyclic-Substituted Piperidine Compound 20 was prepared from thecompound of formula DA except that 2,6-difluoro-1-nitrobenzene was usedin Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 20,1-(1-cyclooctylpiperidin-4-yl)-6-fluoro-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 20: ¹H NMR: δ_(H) (400 MHz,(CD₃)₂SO): 9.55 (1H, bs), 7.30 (1H, m), 7.25 (2H, m), 4.30 (1H, m), 3.50(1H, d, J=20 Hz), 3.10 (2H, m), 2.90 (1H, d, J=20 Hz), 2.67 (1H, m),2.54 (2H, m), 1.95 (4H, m), 1.80-1.40 (14H, m); LC/MS, m/z=388.4 [M+H]⁺.

Heterocyclic-Substituted Piperidine Compound 21 was prepared from thecompound of formula DA except that 2,5-difluoro-1-nitrobenzene was usedin Example 6 in place of 2,4-difluoro-1-nitrobenzene.

The identity of Heterocyclic-Substituted Piperidine Compound 21,1-(1-cyclooctylpiperidin-4-yl)-7-fluoro-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 21: ¹H NMR: δ_(H) (400 MHz,(CD₃)₂SO): 9.65 (1H, bs), 7.55 (1H, m), 7.10 (1H, m), 7.00 (1H, m), 4.27(1H, m), 3.45 (1H, d, J=20 Hz), 3.10 (2H, m), 2.90 (1H, d, J=20 Hz),2.55 (1H, m), 2.38 (2H, m), 2.0-1.80 (4H, m), 1.75-1.35 (14H, m); LC/MS,m/z=520.3 [M+H]⁺.

5.9 Example 9

Heterocyclic-Substituted Piperidine Compound 5, where the 3-positionnitrogen atom was optionally protected by a protecting group asdescribed above, was added to dry DMF and to this mixture was addedsodium hydride. The mixture was warmed under an argon atmosphere thenallowed to cool whereupon 2-bromoacetamide in DMF was added in oneportion. The resulting mixture was stirred until the desired product wasobtained; thereafter, if an optional protecting group was used, it wasremoved. The solvent was removed under reduced pressure to provideresidues that were chromatographed with a silica gel column eluted witha gradient of from 100%:0% EtOAc:MeOH to 0%:100% EtOAc:MeOH. The productfractions were combined and concentrated to dryness under reducedpressure to provide Heterocyclic-Substituted Piperidine Compound 22 as asolid.

The identity of Heterocyclic-Substituted Piperidine Compound 22,2-(5-(1-cyclooctylpiperidin-4-yl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)acetamide,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 22: ¹H NMR: δ_(H) (400 MHz,MeOD): 7.58 (1H, m), 7.50 (1H, m), 7.41 (2H, m), 4.85 (1H, m), 4.49 (1H,m), 4.29 (1H, m), 3.61-3.40 (4H, m), 3.31-3.10 (3H, m), 2.71 (2H, m),2.41 (1H, m), 2.20 (1H, m), 2.01 (2H, m), 1.83 (4H, m), 1.71-1.42 (8H,m); LC/MS (96.1%, t_(r)=4.741 min), m/z=427.4 [M+H]⁺ (Calc: 426.6).

5.10 Example 10

In a manner similar to Example 9, the following Heterocyclic-SubstitutedPiperidine Compounds were prepared from the Heterocyclic-SubstitutedPiperidine Compounds previously synthesized.

Heterocyclic-Substituted Piperidine Compound 23 was prepared by reactingHeterocyclic-Substituted Piperidine Compound 6 with ethyl bromoacetate.

The identity of Heterocyclic-Substituted Piperidine Compound 23,1-(1-cyclooctylpiperidin-4-yl)-7-fluoro-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 23: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 7.65 (1H, m), 7.20 (2H, m), 6.95 (1H, d, J=12 Hz), 4.92 (2H, s),4.80 (1H, m), 4.24 (2H, q, J=10 Hz), 2.96 (2H, m), 2.85-2.60 (3H, m),2.50 (2H, t, J=12 Hz), 1.85-1.40 (16H, m); LC/MS, m/z=441.0 [M+H]⁺.

Heterocyclic-Substituted Piperidine Compound 43 was prepared by reactingHeterocyclic-Substituted Piperidine Compound 6 with ethyl iodide(Sigma-Aldrich).

The identity of Heterocyclic-Substituted Piperidine Compound 43,1-(1-cyclooctylpiperidin-4-yl)-4-ethylquinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 43: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 7.78-7.81 (1H, m), 7.51-7.53 (1H, m), 7.31-7.36 (2H, m), 4.74(1H, m), 4.29 (2H, q, J=7.1 Hz), 3.15 (2H, m), 2.88-3.10 (3H, m),2.66-2.70 (2H, m), 1.84-1.92 (6H, m), 1.52-1.70 (10H, m), 1.36 (3H, t,J=7.1 Hz); LC/MS, m/z=384.3 [M+H]⁺.

Heterocyclic-Substituted Piperidine Compound 44 was prepared by reactingHeterocyclic-Substituted Piperidine Compound 6 with bromoacetonitrile(Sigma-Aldrich).

The identity of Heterocyclic-Substituted Piperidine Compound 44,2-(4-(1-cyclooctylpiperidin-4-yl)-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)acetonitrile,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 44: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 7.71-7.73 (1H, m), 7.41-7.43 (1H, m), 7.28-7.32 (2H, m), 5.21(2H, s), 4.60 (1H, m), 2.96-3.05 (2H, m), 2.79-2.85 (3H, m), 2.53-2.76(2H, m), 1.71-1.81 (6H, m), 1.43-1.59 (10H, m); LC/MS, m/z=395.2 [M+H]⁺.

Heterocyclic-Substituted Piperidine Compound 24 was prepared by reactingHeterocyclic-Substituted Piperidine Compound 12 with bromo acetamide.

The identity of Heterocyclic-Substituted Piperidine Compound 24,2-(4-(1-(1,2-dihydroacenaphthylen-1-yl)piperidin-4-yl)-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)acetamide,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 24: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 8.18-7.05 (12H, m), 5.63 (1H, m), 4.79 (2H, s), 3.98 (1H, m),3.78 (1H, m), 3.56 (1H, s), 3.31 (4H, m), 3.05 (2H, m), 1.91 (2H, m);LC/MS (100%, t_(r)=4.936 min), m/z=455.3 [M+H]⁺ (Calc 454.5).

5.11 Example 11

To a suspension of sodium hydride (0.56 g, 60% in oil, 14.07 mmole) in15 mL of DMF was added a solution of Heterocyclic-Substituted PiperidineCompound 6 (4.0 g, 11.25 mmole) in 10 mL of DMF. The resulting solutionwas allowed to stir for 3 h at about 25° C. A solution of epibromohydrin(2.0 g, 14.63 mmole) in 5 mL of DMF was added dropwise, and theresulting mixture was heated with stirring for at 50° C. After coolingto about 25° C., the reaction mixture was poured into 250 mL of waterand extracted three times with 100 mL of ethyl acetate each time. Thecombined organic layers were dried (MgSO₄) and concentrated underreduced pressure to provide Heterocyclic-Substituted Piperidine Compound25,1-(1-cyclooctylpiperidin-4-yl)-4-(oxiran-2-ylmethyl)quinoxaline-2,3(1H,4H)-dione,as an orange glass.

A solution of Heterocyclic-Substituted Piperidine Compound 25 (0.58 g,1.41 mmole) and pyrrolidine (0.2 g, 2.8 mmole) in 15 mL of DMF washeated at 50° C. for 20 h. The reaction mixture was cooled to atemperature of about 25° C. and poured into 200 μL of water. The aqueousmixture was extracted three times with 100 mL of ethyl acetate eachtime, and the combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure to provide a viscous orange oil. Theoil was chromatographed with a silica gel column eluted with 10:10:80EtOH:TEA:EtOAc to provide a yellow solid which was recrystallized fromethyl acetate to provide 255 mg of Heterocyclic-Substituted PiperidineCompound 26 as an off-white colored solid.

The identity of Heterocyclic-Substituted Piperidine Compound 26,1-(1-cyclooctylpiperidin-4-yl)-4-(2-hydroxy-3-(pyrrolidin-1-yl)propyl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR.

Heterocyclic-Substituted Piperidine Compound 26: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): d 7.7 (m, 2H); 7.2 (m, 2H); 4.9 (m, 2H); 4.4 (bs, 1H); 4.25(m, 1H); 4.1 (bs, 1H); 2.9-2.3 (bm, 13H); 1.8-1.3 (bm, 20H).

5.12 Example 12

In a manner similar to Example 11, the followingHeterocyclic-Substituted Piperidine Compound was prepared fromHeterocyclic-Substituted Piperidine Compound 25 except that morpholinewas used in place of pyrrolidine:

The identity of Heterocyclic-Substituted Piperidine Compound 27,1-(1-cyclooctylpiperidin-4-yl)-4-(2-hydroxy-3-morpholinopropyl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 27: ¹H NMR: δ_(H) (400 MHz,(CD₃)₂SO): 10.75 (1H, bs), 7.95 (1H, bs), 7.68 (1H, dd), 7.27 (3H, m),6.05 (1H, bs), 5.00 (1H, bs), 4.50 (1H, m), 4.17 (2H, m), 3.85 (2H, t),3.80 (2H, m), 3.60-3.00 (15H, m), 2.10 (2H, m), 1.90 (2H, m), 1.80-1.40(12H, m); LC/MS, m/z=499.2 [M+H]⁺.

5.13 Example 13

The compound of formula BB (1.00 g, 3.32 mmol) was added to 50 mL ofDCE. To this was added O-ethyl carbonisocyanatidate (0.0735 mL; 6.64mmol, Sigma-Aldrich). The mixture was sealed in a 100 mL high pressuremicrowave reaction vessel (MicroSYNTH Model HTR-300/6 S), placed into amicrowave reactor (MicroSYNTH), warmed, with stirring, to 150° C., andmaintained at that temperature for 30 min. The reaction mixture wascooled to a temperature of about 25° C., concentrated onto silica toprovide residues that were chromatographed with a silica gel columneluted with a gradient of from 100%:0% EtOAc:MeOH to 0%:100% EtOAc:MeOH.The product fractions were combined and concentrated to dryness underreduced pressure to provide 120 mg of a compound of formula EA as awhite solid (yield 10%).

The identity of the compound of formula EA,-(1-cyclooctylpiperidin-4-yl)-1H-benzo[f][1,3,5]triazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Compound EA: δ_(H) (400 MHz, DMSO-d₆): 10.92 (1H, s), 10.24 (1H, m),7.83 (1H, s), 7.00 (3H, s), 4.62 (1H, m), 3.42 (3H, m), 3.29 (2H, m),2.85 (2H, q), 1.99 (2H, m), 1.85 (2H, m), 1.70 (4H, m), 1.48 (8H, m);LC/MS (100.0%, t_(r)=4.958 min), m/z=371.2 [M+H]⁺ (Calc: 370.5).

5.14 Example 14

A mixture of 4-chloro-2-nitroaniline (EA, 1.726 g, 10 mmol,Sigma-Aldrich), di-tert-butyl dicarbonate ([BOC]₂O, 20 mmol,Sigma-Aldrich) and 4-dimethylaminopyridine (DMAP, catalytic amount,Sigma-Aldrich) in THF (34 mL) was stirred at 90° C. for 1 h. Aftercooling to a temperature of about 25° C., the reaction mixture wasconcentrated under reduced pressure. The residue was chromatographedwith a silica gel column eluted with a gradient of from 1:9EtOAc:n-hexane to 1:4 EtOAc:n-hexane to provide the compound of formulaFB as a colorless solid (yield >99%).

The identity of the compound of formula FB was confirmed using ¹H NMR.

Compound FB: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 8.06 (1H, d, J=4 Hz), 7.60(1H, dd, J=8 Hz, J=4 Hz), 7.27 (1H, d, J=4 Hz), 1.41 (18H, s).

To a mixture of the compound of formula FB (3.70 g, 9.9 mmol) andmethanol (40 mL) was added K₂CO₃ (29.7 nmol) and the reaction mixturewas stirred for 3 h at a temperature of about 25° C. After quenchingwith water (20 mL), the reaction mixture was neutralized with 1N HCl,adjusted to a pH within the range of from about 7 to about 8, extractedwith EtOAc, washed with brine, dried (MgSO₄), and concentrated underreduced pressure. The residue was chromatographed with a silica gelcolumn eluted with a gradient of from 1:19 EtOAc:n-hexane to 3:17EtOAc:n-hexane to provide the compound of formula FC as a yellow solid(yield 90%).

The identity of the compound of formula FC, tert-butyl4-chloro-2-nitrophenylcarbamate, was confirmed using ¹H NMR.

Compound FC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 9.59 (1H, s), 8.57 (1H, d,J=8 Hz), 8.18 (1H, d, J=4 Hz), 7.55 (1H, dd, J=8 Hz, J=4 Hz), 1.54 (9H,s).

A mixture of the compound of formula FC (1.00 g, 3.67 mmol), 2% platinumon carbon (200 mg), and methanol (20 mL) was stirred at a temperature ofabout 25° C. for 2 h in a hydrogen atmosphere. After filtration throughCELITE and washing of the filter pad with EtOAc, the filtrate wasconcentrated under reduced pressure and chromatographed with anamino-silica gel column (Yamazen Corp. W091-01) eluted with a gradientof from 1:4 EtOAc:n-hexane to 1:1 EtOAc:n-hexane to provide the compoundof formula FD as a colorless solid (yield 94%).

The identity of the compound of formula FD, tert-butyl2-amino-4-chlorophenylcarbamate, was confirmed using ¹H NMR and LC/MS.

Compound FD: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.18 (1H, d, J=8 Hz), 6.86(1H, d, J=4 Hz), 6.80 (1H, dd, J=8 Hz, J=4 Hz), 6.25 (1H, s), 1.50 (9H,s); LC/MS, m/z=243.0 [M+H]⁺ (Calc: 242.7).

A mixture of the compound of formula FD (840 mg, 3.46 mmol), thecompound of formula BA (5.54 mmol), sodium triacetoxyborohydride (10.4mmol), acetic acid (3.46 mmol), and chloroform (30 mL) was stirred for16 h at a temperature of about 25° C. After quenching with saturatedNaHCO₃ solution, the mixture was extracted with chloroform, dried(MgSO₄), and concentrated under reduced pressure. The residue waschromatographed with an amino-silica gel column (Yamazen Corp. W091-01)eluted with a gradient of from 3:17 EtOAc:n-hexane to 3:7 EtOAc:n-hexaneto provide the compound of formula FE as a colorless solid (yield 56%).

The identity of the compound of formula FE, tert-butyl4-chloro-2-(1-cyclooctylpiperidin-4-ylamino)phenylcarbamate, wasconfirmed using ¹H NMR.

Compound FE: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.15 (1H, d, J=8 Hz), 6.66(1H, s), 6.65 (1H, s), 5.98 (1H, m), 3.84 (1H, m), 3.23 (1H, m),2.84-2.70 (3H, m), 2.42 (2H, m), 2.04 (2H, m), 1.92-1.39 (24H, m).

To a suspension of the compound of formula FE (844 mg, 1.93 mmol) in1,4-dioxane (8 mL) was added 4N HCl in 1,4-dioxane (19.3 mmol) and thereaction mixture was stirred for 2 h at a temperature of about 25° C.Thereafter, the reaction mixture was heated to 50° C. and stirred for 30min. After concentration under reduced pressure, the mixture wasneutralized with 28% aqueous ammonia to adjust the pH within the rangefrom about 13 to about 14. After extraction with chloroform, the organiclayer was dried (MgSO₄) and concentrated under reduced pressure toprovide the compound of formula FF as a brown solid (yield >99%).

The identity of the compound of formula FF,5-chloro-N4-(1-cyclooctylpiperidin-4-yl)benzene-1,2-diamine, wasconfirmed using ¹H NMR.

Compound FF: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 6.63-6.58 (3H, m), 5.98(1H, m), 3.37 (1H, m), 3.22 (2H, m), 2.85-2.83 (2H, m), 2.44 (1H, d,J=12 Hz), 2.41 (2H, t, J=12 Hz), 2.08 (2H, d, J=12 Hz), 1.83-1.45 (17H,m).

To a mixture of the compound of formula FF (168 mg, 0.5 mmol) andmethylene chloride (3 mL) at a temperature of 0° C. was added dropwiseover a 10 minute period a mixture of methyl 2-chloro-2-oxoacetate (0.55mmol, Sigma-Aldrich) and methylene chloride (1.5 mL). The resultingreaction mixture was stirred at 0° C. for 30 min. After quenching withsaturated NaHCO₃ solution, the mixture was extracted with chloroform,dried (MgSO₄), and concentrated under reduced pressure to provide anoil. The oil was chromatographed with a silica gel column eluted with agradient of from 97%:3% CHCl₃:MeOH to 90%:10% CHCl₃:MeOH to provide 181mg of the compound of formula FG as a yellow amorphous solid (yield86%).

The identity of the compound of formula FG, methyl2-(4-chloro-2-(1-cyclooctylpiperidin-4-ylamino)phenylamino)-2-oxoacetate,was confirmed using ¹H NMR and LC/MS.

Compound FG: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 8.80 (1H, s), 7.43 (1H, d,J=8.7 Hz), 6.79 (1H, d, J=8.7 Hz), 6.69 (1H, d, J=2.4 Hz), 3.98 (3H, s),3.40-2.83 (7H, m), 2.84-1.45 (17H, m); LC/MS, m/z=421.8 [M+H]⁺ (Calc:422.0).

To a mixture of the compound of formula FG (259 mg, 0.614 mmol) andethanol (6 mL) was added sodium methoxide (133 mg, 2.46 mmol,Sigma-Aldrich) at a temperature of about 25° C. The reaction mixture washeated to 70° C. then stirred at that temperature for 3 h. Afterconcentration under reduced pressure, 1N aqueous HCl was added to adjustthe pH within the range of from about 2 to about 3; thereafter a whiteprecipitate formed. The precipitate was filtered, washed with water,washed with methanol, and dried under reduced pressure at 50° C. toprovide 171 mg of the hydrochloride of Heterocyclic-SubstitutedPiperidine Compound 45 as a colorless solid (yield 65%).

The identity of Heterocyclic-Substituted Piperidine Compound 45,7-chloro-1-(1-cyclooctylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 45: ¹H NMR: δ_(H) (300 MHz,MeOD): 7.78 (1H, d, J=1.8 Hz), 7.25 (1H, dd, J=2 Hz, J=8.7 Hz), 7.18(1H, d, J=8.7 Hz), 4.77 (1H, m), 3.60-3.37 (6H, m), 3.32-3.10 (3H, m),2.09-1.48 (15H, m); LC/MS (97%, t_(r)=2.09 min), m/z=390.0 [M+H]⁺ (Calc:389.9).

5.15 Example 15

Heterocyclic-Substituted Piperidine Compound 46 was prepared in a mannersimilar to Heterocyclic-Substituted Piperidine Compound 45 in Example 14except that 4-bromo-2-nitroaniline (Sigma-Aldrich) was used in place of4-chloro-2-nitroaniline.

The identity of Heterocyclic-Substituted Piperidine Compound 46,7-bromo-1-(1-cyclooctylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 46: ¹H NMR: δ_(H) (300 MHz,MeOD): 7.88 (1H, d, J=1.8 Hz)), 7.38 (1H, dd, J=1.8 Hz, J=8.7 Hz), 7.13(1H, d, J=8.7 Hz), 4.81 (1H, m), 3.60-3.34 (6H, m), 3.25-3.10 (3H, m),1.48-2.12 (15H, m); LC/MS (97%, t_(r)=2.10 min), m/z=435.9 [M+H]⁺ (Calc:434.4).

To a mixture of the hydrochloric of Heterocyclic-Substituted PiperidineCompound 46 (120 mg, 0.25 mmol, 1 eq.), morpholine (0.61 mmol, 2.4 eq.,Wako Pure Chemical Industries, Ltd., Osaka, Japan),tris(dibenzylideneacetone) dipalladium (Pd₂(DBA)₃, 0.013 mmol, 0.05 eq.,Sigma-Aldrich), (2-biphenyl)-dicyclohexylphosphine (BDCHP, 0.013 mmol,0.05 eq., Sigma-Aldrich), and DMF (3 mL) in a tube at a temperature ofabout 25° C. was added a 1 mol/L THF solution of lithiumhexamethyldisilazide (LHMDS, 1.15 mmol, 4.6 eq., Sigma-Aldrich) and thetube was sealed. Thereafter, under microwave irradiation, the reactionmixture was stirred for 30 min at 150° C. After cooling to a temperatureof about 25° C., to the reaction mixture was added to 2N HCl (0.5 mL)and the mixture was stirred for 5 min. After concentration under reducedpressure, the resulting black oil was chromatographed with anamino-silica gel column (Yamazen Corp. W09′-01) eluted with a gradientof from 90%:10% EtOAc:MeOH to 70%:30% EtOAc:MeOH to provide a yellowsolid. The solid was recrystallized with 4:1 MeOH:EtOAc to provideHeterocyclic-Substituted Piperidine Compound 47 as a pale yellow solid(yield 38%).

The identity of Heterocyclic-Substituted Piperidine Compound 47,1-(1-cyclooctylpiperidin-4-yl)-7-morpholinoquinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 47: ¹H NMR: δ_(H) (300 MHz,CD₃OD): 7.12-7.09 (2H, m), 6.88 (1H, dd, J=2.4 Hz, J=8.7 Hz), 4.88 (1H,m), 3.86 (4H, t, J=4.5 Hz), 3.17 (4H, t, J=4.5 Hz), 3.02-2.99 (2H, m),2.84-2.74 (4H, m), 2.58-2.50 (2H, m), 1.89-1.54 (15H, m); LC/MS,m/z=441.0 [M+H]⁺ (Calc: 440.6).

5.16 Example 16

The compound of formula GA, tert-butyl4-bromo-2-(1-cyclooctylpiperidin-4-ylamino)phenylcarbamate, was preparedin a manner similar to the compound of formula FE in Example 14 exceptthat 4-bromo-2-nitroaniline was used in place of4-chloro-2-nitroaniline.

To a mixture of the compound of formula GA (300 mg, 0.624 mmol),pyridine (1.25 mmol), and methylene chloride (8 mL) at a temperature of0° C. was added dropwise over a 10 minute period a mixture of ethyl3-chloro-3-oxopropanoate (0.66 mmol, Sigma-Aldrich) in methylenechloride (2 mL). The resulting reaction mixture was stirred at 0° C. for1 h. After quenching with water and extraction with chloroform, theorganic layer was dried (MgSO₄) and concentrated under reduced pressure.The resulting oil was chromatographed with an amino-silica gel column(Yamazen Corp. W091-01) eluted with a gradient of from 3:97EtOAc:n-hexane to 1:4 EtOAc:n-hexane to provide 166 mg of the compoundof formula GB as a colorless amorphous solid (yield 44%).

The identity of the compound of formula GB, ethyl3-((5-bromo-2-(tert-butoxycarbonylamino)phenyl)(1-cyclooctylpiperidin-4-yl)amino)-3-oxopropanoate,was confirmed using ¹H NMR.

Compound GB: ¹H NMR: δ_(H) (400 MHz, DMSO): 8.84 (1H, s), 7.69 (1H, dd,J=8.4 Hz), 7.58 (1H, d, J=8.5 Hz), 7.26 (1H, d, J=4 Hz), 4.21 (1H, m),3.99 (2H, q, J=8 Hz), 2.97 (2H, m), 2.64 (2H, m), 2.44 (1H, s), 2.15(2H, m), 1.77-1.32 (14H, m), 1.14 (3H, t, J=8 Hz).

To a mixture of the compound of formula GB (160 mg, 0.27 mmol) and1,4-dioxane (3 mL) at a temperature of about 25° C. was added 4N HCl in1,4-dioxane (5.4 mmol). The resulting reaction mixture was cooled to 0°C. and stirred for 2 h. Thereafter, the reaction mixture was warmed to atemperature of about 25° C. and stirred for 1 h. After quenching withwater, the mixture was neutralized with 28% aqueous ammonia to adjustthe pH within the range of from about 13 to about 14. Thereafter, Afterchloroform was used in an extraction, the organic layer was dried(MgSO₄), and concentrated under reduced pressure. The resulting oil waschromatographed with a silica gel column eluted with a gradient of from97%:3% CHCl₃:MeOH to 90%:10% CHCl₃:MeOH to provide 30 mg of the compoundof formula GC as a colorless amorphous solid (yield 23%).

The identity of the compound of formula GC, ethyl3-((2-amino-5-bromophenyl)(1-cyclooctylpiperidin-4-yl)amino)-3-oxopropanoate,was confirmed using ¹H NMR and LC/MS.

Compound GC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.25 (1H, d, J=8 Hz), 7.07(1H, d, J=2 Hz), 6.65 (1H, d, J=8 Hz), 4.11 (2H, q, J=8 Hz), 3.99 (1H,s), 3.13 (2H, s), 2.95-2.23 (7H, m), 2.02-1.38 (14H, m), 1.22 (3H, t,J=8 Hz); LC/MS, m/z=496.0 [M+H]⁺ (Calc: 494.5).

To a mixture of the compound of formula GC (65 mg, 0.13 mmol) in ethanol(4 mL) at a temperature of about 25° C. was added sodium methoxide (28mg, 0.53 mmol). The reaction mixture was heated to 70° C. then stirredat that temperature for 1 h. After concentration under reduced pressure,the oil obtained was chromatographed by preparative thin layerchromatography (TLC, eluted with 10:1:0.1 CHCl₃:MeOH:aqueous ammonia) toprovide a colorless amorphous solid. To the solid was added 4N HCl in1,4-dioxane. The resulting mixture was concentrated under reducedpressure. The residue was dried under reduced pressure at 50° C. toprovide 50 mg of the hydrochloride of Heterocyclic-SubstitutedPiperidine Compound 48 as a colorless solid (yield 79%).

The identity of Heterocyclic-Substituted Piperidine Compound 48,8-bromo-1-(1-cyclooctylpiperidin-4-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 48: ¹H NMR: δ_(H) (300 MHz,MeOD): 7.67 (1H, d, J=2.4 Hz), 7.50 (1H, dd, J=2.4 Hz, J=8.4 Hz), 7.14(1H, d, J=8.4 Hz), 4.22 (1H, m), 3.59-3.02 (8H, m), 2.65 (2H, m),2.20-1.41 (15H, m); LC/MS (98%, t_(r)=2.05 min), m/z=449.9 [M+H]⁺ (Calc:448.4).

5.17 Example 17

Cyclooctylamine (1,155 g, 1218.5 mmol, Sigma-Aldrich) was dissolved inacetonitrile (500 mL). Methyl acrylate (HB, 470 g, 5460 mmol,Sigma-Aldrich) was added, followed by the addition of bismuth triflate(15 g, Sigma-Aldrich), and the mixture heated under reflux for 18 h. Themixture was concentrated under reduced pressure and was chromatographedby flash silica eluted with hexanes, followed by eluting with 10:1hexanes:EtOAc to provide 360 g of a compound of formula HC as acolorless oil (yield >99%).

The identity of the compound of formula HC, dimethyl3,3′—(cyclooctylazanediyl)dipropanoate, was confirmed using ¹H NMR.

Compound HC: ¹H NMR: δ (400 MHz, CDCl₃): 3.68 (3H, s), 2.70 (2H, t, J=10Hz), 2.65 (1H, m), 2.40 (2H, t, J=10 Hz), 1.75-1.35 (14H, m).

The compound of formula HC (10 g, 334 mmol) was dissolved in dry toluene(2 L) and cooled to 0° C. under a nitrogen atmosphere. Sodiumtert-butoxide (41.7 g, 434.2 mmol, Sigma-Aldrich) was added and themixture was stirred for 3 h at 0° C. When LC/MS showed about 10-20% ofthe compound of formula HC remained, a further portion of sodiumtert-butoxide (10 g) was added and stirring was continued for anadditional 1 h. The mixture was poured into water (2 L) and the organicphase was separated. The aqueous phase was extracted with ethyl acetate(1 L). The organic phases were combined, dried (MgSO₄), and concentratedunder reduced pressure to provide a yellow oil which was chromatographedby flash silica eluted with 5:1 hexanes:EtOAc to provide 60 g of thecompound of formula HD as a yellow oil (yield 68%) which slowlysolidified upon standing.

The identity of the compound of formula HD, methyl1-cyclooctyl-4-oxopiperidine-3-carboxylate, was confirmed using TLC.

Compound HD: TLC (SiO₂) 5:1 Hexanes:EtOAc: Rf=0.25 with UV detection,Dragendorff's reagent.

The compound of formula HD (20 g, 75.4 mmol) and o-phenylenediamine(16.29 g, 150.8 mmol) were dissolved in toluene (200 mL). Acetic acid (1mL) was added and the mixture was heated under reflux with azeotropicremoval of water for 1 h. The mixture was concentrated under reducedpressure and the residue was chromatographed by flash silica eluted with100:2 EtOAc:AcOH, followed by eluting with 100:2:5 EtOAc:AcOH:MeOH toprovide an orange gum. The gum was dissolved in ethyl acetate (400 mL)and treated with potassium carbonate/water until neutralized, i.e., hada pH greater than 7. The organic phase was separated, dried (MgSO₄) andconcentrated under reduced pressure to provide and orange gum whichcrystallized upon standing. Trituration with 1:10 hexanes:diethyl ether(200 mL) provided 17 g of the compound of formula HE as a buff-coloredsolid (yield 63%).

The identity of the compound of formula HE, methyl4-(2-aminophenylamino)-1-cyclooctyl-1,2,5,6-tetrahydropyridine-3-carboxylate,was confirmed using ¹H NMR.

Compound HE: ¹H NMR: δ (400 MHz, CDCl₃): 9.8 (1H, s), 7.05 (1H, t, J=10Hz), 6.95 (1H, d, J=10 Hz), 6.75-6.65 (2H, m), 3.85 (2H, bs), 3.70 (3H,s), 3.32 (2H, s), 2.72 (1H, m), 2.50 (2H, t, J=10 Hz), 2.25 (2H, t, J=10Hz), 1.80-1.40 (14H, m).

5.18 Example 18

The compound of formula HE (11 g, 30.77 mmol), prepared in Example 17,was dissolved in dichloromethane (2 L) and added dropwise to a cold,−78° C., mixture of oxalyl dichloride (2.86 mL, 33.85 mmol,Sigma-Aldrich) in dichloromethane (6 L) over 3 h. Thereafter withstirring, over 18 h the resulting mixture was allowed to warm to atemperature of about 25° C. The mixture was concentrated under reducedpressure and the residue was chromatographed by flash silica eluted with400:10:1 EtOAc:MeOH:ammonia to provide a yellow solid. This solid wastriturated with diethyl ether (30 mL) to provide 4.0 g ofHeterocyclic-Substituted Piperidine Compound 49 as a light yellow solid(yield 32%).

The identity of Heterocyclic-Substituted Piperidine Compound 49, methyl1-cyclooctyl-4-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate,was confirmed using ¹H NMR.

Heterocyclic-Substituted Piperidine Compound 49: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 10.7 (1H, bs), 7.28 (1H, m), 7.15 (2H, m), 7.05 (1H, m), 3.55(2H, m), 3.50 (3H, m), 2.90 (3H, m), 2.50 (2H, m), 1.90-1.40 (14H, m).

Heterocyclic-Substituted Piperidine Compound 49 (100 mg, 0.24 mmol) wasdissolved in methanol (1 mL). Crushed sodium hydroxide (50 mg, 1.21mmol) was dissolved in water (0.3 mL), added to the methanol, and theresulting mixture stirred for 1 h. After this time a solid hadprecipitated. The mixture was filtered and the filter cake was washedwith methanol (3 mL) and concentrated under reduced pressure to provide105 mg of Heterocyclic-Substituted Piperidine Compound 50 as abuff-colored solid (yield >99%).

The identity of Heterocyclic-Substituted Piperidine Compound 50, methyl1-cyclooctyl-4-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid sodium salt, was confirmed using ¹H NMR.

Heterocyclic-Substituted Piperidine Compound 50: ¹H NMR: δ (400 MHz,(CD₃)₂SO): 7.00 (1H, m), 6.90 (1H, m), 6.85 (1H, m), 6.77 (1H, m), 3.40(1H, m), 2.65 (4H, m), 2.20 (1H, m), 2.00 (1H, m), 1.80-1.40 (14H, m).

The Heterocyclic-Substituted Piperidine Compound 49 (100 mg, 0.24 mmol)was dissolved in dry DMF (2 mL) under a nitrogen atmosphere. Sodiumhydride (95%, Sigma-Aldrich) was added and the mixture was heated to 90°C. for 1 h then cooled to 50° C. with stirring. Iodomethane (18 μL,0.292 mmol, Sigma-Aldrich) was added and the mixture stirred for 3 h.LC/MS showed greater than 75% conversion after this time. The mixturewas partitioned between diethyl ether (100 mL) and 1M potassiumcarbonate (100 mL) and the organic phase separated, dried (MgSO₄), andconcentrated under reduced pressure to provide a residue. The residuewas chromatographed by flash silica eluted with 1:1 EtOAc:hexanes,followed by eluting with 100:100:10:1 EtOAc:hexanes:MeOH:ammonia toprovide 35 mg of Heterocyclic-Substituted Piperidine Compound 51 as ayellow solid.

The identity of Heterocyclic-Substituted Piperidine Compound 51, methyl1-cyclooctyl-4-(4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate,was confirmed using ¹H NMR and TLC.

Heterocyclic-Substituted Piperidine Compound 51: ¹H NMR: δ (400 MHz,CDCl₃): 7.25 (1H, m), 7.18 (2H, m), 7.12 (1H, m), 3.70 (3H, S), 3.56(2H, m), 3.50 (3H, s), 2.85 (1H, m), 2.50 (2H, m), 1.80 (4H, m),1.70-1.45 (10H, m); TLC (SiO₂) 100:100:10:1 EtOAc:hexanes:MeOH:ammonia:Rf=0.22 with UV detection, Dragendorff's reagent.

5.19 Example 19

The compound of formula IB, (bromomethyl)benzene (6.5 g, 38 mmol,Sigma-Aldrich), was added to a mixture of the compound of formula IA,(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (5 g, 36 mmol,Sigma-Aldrich), in acetone (100 mL) over 30 min at a temperature ofabout 25° C. The resulting mixture was stirred at a temperature of about25° C. for 1 h then at 38° C. for 2 h. Thereafter, the mixture wascooled to a temperature of about 25° C., filtered, and washed twice withhexanes (10 mL for each wash) to provide 10 g of the compound of formulaIC as white solid (yield 85%).

The compound of formula IC,(1R,5S)-8-benzyl-8-methyl-3-oxo-8-azoniabicyclo[3.2.1]octane bromide (5g, 16.1 mmol), was mixed with 40 mL ethanol and 20 mL of water. Thismixture was added to a mixture at 70° C. of the compound of formula HA(2.0 g, 16 mmol), and K₂CO₃ (0.2 g, 1.4 mmol) in ethanol (150 mL) over30 min. After 3 h at 70° C., the reaction mixture was cooled to atemperature of about 25° C. and concentrated. The residue was treatedwith water (50 mL), and extracted three times with chloroform (100 mLfor each extraction). The combined organic layers were washed with brine(50 mL), and concentrated to provide 3.5 g of the compound of formula ID(yield 92%).

Sodium triacetoxyborohydride (50 mmol) was added to a mixture of thecompound of formula II),(1R,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-one (3 g, 12.8 mmol),and o-phenylenediamine (3 g, 27.8 mmol) in 100 mL of methylene chlorideat a temperature of about 25° C. Thereafter, 3 mL of acetic acid wasadded. The resulting mixture was stirred at a temperature of about 25°C. for about 16 h. Thereafter, methanol (2 mL) and water (25 mL) wereadded and the mixture was neutralized with 28% aqueous ammonia to adjustthe pH to about 8. The organic layer was separated, washed with brine(10 mL), concentrated, and chromatographed with a silica gel columneluted with 10:1:1 EtOAc:MeOH:TEA to provide 2.8 g of a mixture of thecompounds of formula IE and IF as brown oil (yield 68%).

The identity of the compound of formula IE,N¹—((1R,3r,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,was confirmed using TLC.

Compound IF: TLC (SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.6 with UVdetection, Dragendorffs reagent.

The identity of the compound of formula IF,N¹—((1R,3s,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,was confirmed using TLC.

Compound IF: TLC (SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.4 with UVdetection, Dragendorffs reagent.

A mixture of the above brown oil (0.3 g, containing the compounds offormula IE and ) in 20 mL of diethyl oxalate (Sigma-Aldrich) was heatedat 140° C. for 16 h. After cooling to a temperature of about 25° C., thereaction mixture was diluted with EtOAc, washed with 30 mL of 2N aqueousNaOH and brine (20 mL), concentrated, and chromatographed with a silicagel column eluted with 5:5:0.5:0.5 EtOAc:hexane:MeOH:TEA to provide 60mg and 20 mg of the two Heterocyclic-Substituted Piperidine Compounds 52and 53, respectively, each as a white solid (yield 18% and 6%,respectively).

The identity of Heterocyclic-Substituted Piperidine Compound 52,1-((1R,3r,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 52: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃)): 7.51 (1H, d, J=7.9 Hz), 7.11-7.21 (m, 3H), 5.16-5.24 (m,1H), 4.08 (br, 2H), 2.9 (br, 1H), 2.56-2.64 (m, 2H), 2.06-2.26 (m, 6H),1.72-1.96 (m, 6H), 1.32-1.62 (m, 8H); LC/MS (100%, t_(r)=4.988 min),m/z=382.4 [M+H]⁺ (Calc: 381.5); TLC (SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH:Rf=0.5 with UV detection, Dragendorff's reagent.

The identity of Heterocyclic-Substituted Piperidine Compound 53,1-((1R,3s,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 53: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃)): 7.62 (br, 1H), 7.21-7.24 (m, 3H), 4.95 (br, 1H), 3.75(br, 2H), 3.36 (br, 1H), 2.91-2.98 (m, 2H), 2.06-2.16 (m, 2H), 1.42-1.96(m, 18H); LC/MS (100%, t_(r)=4.718 min), m/z=382.2 [M+H]⁺ (Calc: 381.5);TLC (SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.45 with UV detection,Dragendorff's reagent.

5.20 Example 20

In a manner similar to Example 19, the followingHeterocyclic-Substituted Piperidine Compounds were prepared fromcompounds previously synthesized.

Heterocyclic-Substituted Piperidine Compounds 54 and 55 were preparedfrom the compounds of formula IE and IF, respectively, except thatmalonyl dichloride was used in Example 19 in place of diethyl oxalate.

The identity of Heterocyclic-Substituted Piperidine Compound 54,1-((1R,3r,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 54: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃)): 7.38-7.42 (m, 1H), 7.28-7.32 (m, 2H), 7.16-7.25 (m, 1H),4.18-4.24 (m, 1H), 3.56-3.68 (m, 2H), 3.36 (1H, d, J=12.4 Hz), 3.07 (d,1H, J=12.3 Hz), 2.52-2.61 (m, 1H), 2.2-2.4 (m, 3H), 1.96-2.02 (m, 3H),1.44-1.82 (m, 16H); LC/MS (100%, t_(r)=5.054 min), m/z=396.3 [M+H]⁺(Calc: 395.5); TLC (SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.7 with UVdetection, Dragendorffs reagent.

The identity of Heterocyclic-Substituted Piperidine Compound 55,1-((1R,3s,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 55: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃)): 7.38-7.42 (m, 1H), 7.28-7.32 (m, 2H), 7.16-7.25 (m, 1H),4.42-4.46 (m, 1H), 3.56-3.68 (m, 2H), 3.36 (1H, d, J=12.4 Hz), 3.21-3.24(m, 1H), 3.07 (d, 1H, J=12.3 Hz), 2.45-2.58 (m, 1H), 1.44-1.84 (m, 18H);LC/MS (98.6%, t_(r)=5.000 min), m/z=396.3 [M+H]⁺ (Calc: 395.5); TLC(SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.5 with UV detection, Dragendorff'sreagent.

Heterocyclic-Substituted Piperidine Compounds 56 and 57 were preparedaccording to the procedure in Example 19 except that9-methyl-9-azabicyclo[3.3.1]nonan-3-one (Pseudo-Pelletierine, obtainedfrom Oakwook Products, Inc., West Columbia, S.C.) was used in place ofthe compound of formula IA to prepare the compounds of formula JA and JBwhich were used to prepare Heterocyclic-Substituted Piperidine Compounds56 and 57, respectively.

The identity of Heterocyclic-Substituted Piperidine Compound 56,1-((1R,3r,5S)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)quinoxaline-2,3(1H,4.1)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 56: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃): 7.5-7.55 (m, 1H), 7.2-7.26 (m, 3H), 5.08 (br, 1H),3.52-3.6 (m, 2H), 3.08-3.16 (m, 1H), 2.64-2.76 (m, 2H), 2.44-2.52 (m,1H), 2.08-2.16 (m, 2H), 1.48-1.82 (m, 17H), 1.12-1.2 (m, 2H); LC/MS(97.9%, t_(r)=4.450 min), m/z=396.3 [M+H]⁺ (Calc: 395.5); TLC (SiO₂)10:2:1 EtOAc-MeOH:NH₄OH: Rf=0.62 with UV detection, Dragendorffsreagent.

The identity of Heterocyclic-Substituted Piperidine Compound 57,1-((1R,3s,5S)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 57: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃): 7.72 (br, 1H), 7.21-7.26 (m, 3H), 5.8 (br, 1H), 4.53 (br,2H), 3.49-3.54 (m, 2H), 3.37-3.41 (m, 1H), 2.97-3.06 (m, 2H), 2.04-2.12(m, 3H), 1.52-1.86 (m, 19H), 1.12-1.2 (m, 2H); LC/MS (97%, t_(r)=4.936min), m/z=396.3 [M+H]⁺ (Calc: 395.5); TLC (SiO₂) 10:2:1EtOAc:MeOH:NH₄OH: Rf=0.3 with UV detection, Dragendorff's reagent.

Heterocyclic-Substituted Piperidine Compounds 58 and 59 were preparedaccording to the procedure in Example 19 except that9-methyl-9-azabicyclo[3.3.1]nonan-3-one was used in place of thecompound of formula IA to prepare the compounds of formula JA and JB.Thereafter, in a manner similar to Example 2, Heterocyclic-SubstitutedPiperidine Compounds 58 and 59 were prepared from malonyl dichloride andthe compounds of formula JA and JB, respectively.

The identity of Heterocyclic-Substituted Piperidine Compound 58,1-((1R,3r,5S)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 58: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃)): 7.46-7.50 (m, 1H), 7.27-7.31 (m, 2H), 7.13-7.17 (m, 1H),4.42-4.48 (m, 1H), 3.44-3.64 (m, 2H), 3.3-3.33 (m, 1H), 3.16-3.21 (m,1H), 2.92-2.98 (m, 1H), 2.12-2.22 (m, 4H), 1.35-1.75 (m, 20H); LC/MS(100%, t_(r)=5.299 min), m/z=410.2 [M+H]⁺ (Calc: 409.6); TLC (SiO₂)10:2:1 EtOAc:MeOH:NH₄OH: Rf=0.71 with UV detection, Dragendorff'sreagent.

The identity of Heterocyclic-Substituted Piperidine Compound 59,1-((1R,3s,5S)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 59: LC/MS (184%,t_(r)=5.116 min), m/z=410.2 [M+H]⁺ (Calc: 409.6); TLC (SiO₂) 10:2:1EtOAc:MeOH:NH₄OH: Rf=0.18 with UV detection, Dragendorff's reagent.

The compound of formula KA, methyl3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate, was prepared by theprocedure provided in N. Ctamer, S. Laschat, A. Baro and W. Frey,Synlett 2175-2177 (2003).

A mixture of the compound of formula KA (1.0 g, 5.5 mmol),o-phenylenediamine (1.2 g, 11 mmol), NaB(OAc)₃H (2.5 g, 12.5 mmol) andacetic acid (0.7 g, 11 mmol) in 40 mL of DCE was stirred under nitrogenat a temperature of about 25° C. for 36 h. Methanol (1 mL) was addedslowly such that the temperature of the reaction mixture did not exceed25° C. The reaction mixture was washed with water (20 mL), extractedthree times with DCM (20 mL for each extraction), concentrated underreduced pressure, and chromatographed with a silica gel column elutedwith 10:3 EtOAc:MeOH to provide a mixture of the compounds of formulasKB and KC.

The mixture of the compounds of formulas KB and KC in 40 mL of diethyloxalate was heated at 150° C. for 16 h. After cooling to a temperatureof about 25° C., the solid was filtered off and the mixture concentratedunder reduced pressure. The residue was chromatographed with a silicagel column eluted with 10:3 EtOAc:MeOH to provide a mixture of thecompounds of formulas KD and KE.

Iodotrimethylsilane (TMSI, 0.2 mL, Sigma-Aldrich) was added to a mixtureof the compounds of formulas KD and KE (110 mg, 0.4 mmol) in 10 mL ofdry DCM at a temperature of about 25° C. Thereafter, the reactionmixture was heated and shaken at 50° C. for 2 h. After cooling to atemperature of about 25° C., acetic acid (0.2 mL) was added to thereaction mixture and it was concentrated under reduced pressure toprovide a mixture of the compounds of formulas KF and KG as a brownsolid.

The mixture of the compounds of formulas KF and KG was added toacetonitrile (4 mL). 3-Bromo-cyclooctene (K, 100 mg, 0.5 mmol, preparedaccording to the method in M. Sellen et al., J. Org. Chem. 56: 835(1991)), TEA (0.1 mL), potassium iodide (20 mg), and potassium carbonate(0.4 g) were then added to the acetonitrile. The resulting reactionmixture was shaken at 60° C. for 16 h. After cooling to a temperature ofabout 25° C., water (10 mL) was added to the reaction mixture and it wasextracted three times with DCM (10 mL for each extraction), concentratedunder reduced pressure, and chromatographed with a silica gel columneluted with 10:1:0.1 EtOAc:MeOH:TEA to provide 20 mg and 14 mg of thetwo Heterocyclic-Substituted Piperidine Compounds 60 and 61,respectively, each as a white solid (yield 15% and 11%, respectively).

The identity of Heterocyclic-Substituted Piperidine Compound 60,(Z)-1-(8-(Cyclooct-2-enyl)-8-azabicyclo[3.2.1]oct-6-en-3-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 60: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃)): 7.83 (1H, d, J=8.3 Hz), 7.21-7.28 (m, 3H), 6.32-6.41 (m,2H), 6.02-6.08 (m, 2H), 5.72-5.8 (m, 1H), 4.44-4.64 (m, 3H), 2.42-2.54(m, 3H), 2.02-2.14 (m, 3H), 1.54-1.78 (m, 5H), 1.28-1.36 (m, 3H); LC/MS(100%, t_(r)=4.977 min), m/z=378.1 [M+H]⁺ (Calc: 377.5); TLC (SiO₂)10:2:1 EtOAc:MeOH:NH₄OH: Rf=0.51 with UV detection, Dragendorffsreagent.

The relative structure of Heterocyclic-Substituted Piperidine Compound60, trans-H1 to bridge, was assigned based on 2D NMR spectrometry.

The identity of Heterocyclic-Substituted Piperidine Compound 61,(Z)-1-(8-(Cyclooct-2-enyl)-8-azabicyclo[3.2.1]oct-6-en-3-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR, LC/MS and TLC.

Heterocyclic-Substituted Piperidine Compound 61: ¹H NMR: δ_(H) (400 MHz,(CD₃OD+CDCl₃)): 7.52-7.56 (m, 1H), 7.18-7.25 (m, 3H), 6.28-6.34 (m, 2H),5.84-5.92 (m, 1H), 5.32-5.43 (m, 1H), 4.54-4.58 (m, 1H), 4.1-4.14 (m,1H), 2.62-2.68 (m, 1H), 2.08-2.14, (m, 1H), 1.94-1.96 (m, 1H), 1.72-1.82(m, 3H), 1.52-1.62 (m, 4H), 1.22-1.35 (m, 5H); LC/MS (100%, t_(r)=4.777min), m/z=378.1 [M+H]⁺ (Calc: 377.5); TLC (SiO₂) 10:2:1EtOAc:MeOH:NH₄OH: Rf=0.23 with UV detection, Dragendorff's reagent.

The relative structure of Heterocyclic-Substituted Piperidine Compound61, cis-H1 to bridge, was assigned based on 2D NMR spectrometry.

5.22 Example 22

To a mixture of N,N-diisopropylamine (6.81 mL, 48.6 mmol) in THF (100mL) at a temperature of 0° C. was added dropwise a mixture of 1.6Nn-butyl lithium (Sigma-Aldrich) in THF (30.4 mL, 48.6 mmol). Theresulting mixture was stirred at 0° C. for 15 min. After cooling to atemperature of −78° C., a mixture of the compound of formula LA(1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate, 10.0 g, 38.9 mmol,Sigma-Aldrich) in THF (50 mL) was added dropwise over a 30 min period.After being stirred at −78° C. for 2 h, a mixture of methyl iodide (4.84mL, 77.7 mmol) in THF (30 mL) was added dropwise at −78° C. The mixturewas allowed to warm to a temperature of about 25° C. for 16 h. Afterquenching with saturated aqueous NH₄Cl, the mixture was partitionedbetween THF and saturated aqueous NH₄Cl. The organic layer wasseparated, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The product was chromatographed (COMBIFLASH) with a gradientof from 0%:100% EtOAc:hexanes to 50%:50% EtOAc:hexanes to provide, afterconcentration under reduced pressure, 8.10 g of the compound of formulaLB as a pale yellow solid (yield 76.8%).

The identity of the compound of formula LB, 1-tert-butyl 4-ethyl4-methylpiperidine-1,4-dicarboxylate, was confirmed using ¹H NMR.

Compound LB: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 4.16 (2H, q, J=7.1 Hz),3.76 (2H, br), 2.95-3.01 (2H, m), 2.05-2.08 (2H, m), 1.45 (9H, s),1.32-1.43 (2H, m), 1.26 (3H, t, J=7.1 Hz), 1.20 (3H, s).

A mixture of the compound of formula LB (4.10 g, 15.1 mmol) and lithiumhydroxide (2.17 g, 90.6 mmol) in methanol (30 mL)/H₂O (20 mL) wasstirred at a temperature of about 25° C. for 16 h. After evaporation todryness, the residue was partitioned between DCM and brine. The organiclayer was separated, dried (MgSO₄), filtered, and concentrated underreduced pressure to provide 3.38 g of the compound of formula LC as awhite solid (yield 92.0%).

The identity of the compound of formula LC,1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid, wasconfirmed using ¹H NMR and LC/MS.

Compound LC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 3.60-3.70 (2H, m),3.03-3.09 (2H, m) 2.05-2.08 (2H, m), 1.45 (9H, s), 1.36-1.45 (2H, m),1.27 (3H, m); LC/MS (100%, t_(r)=2.500 min), m/z=266.1 [M+Na]⁺ (Calc:243).

To a mixture of the compound of formula LC (2.00 g, 8.22 mmol) and TEA(1.72 mL, 12.3 mmol) in toluene (20 mL) at a temperature of about 25° C.was added the compound of formula LD (diphenylphosphoryl azide (“DPPA”),2.42 mL, 11.2 mmol, Sigma-Aldrich). The mixture was stirred at atemperature of about 25° C. for 18 h. After evaporation to dryness, theresidue was partitioned between EtOAc and 1N aqueous NaOH. The organiclayer was separated, dried (Na₂SO₄), filtered, and concentrated todryness under reduced pressure. The residue was chromatographed(COMBIFLASH) with a gradient of from 0%:100% EtOAc:hexanes to 50%:50%EtOAc:hexanes to provide, after concentration under reduced pressure,2.00 g of the compound of formula LE as colorless oil (yield 70.1%).

The identity of the compound of formula LE, tert-butyl4-(benzyloxycarbonylamino)-4-methylpiperidine-1-carboxylate, wasconfirmed using ¹H NMR and LC/MS.

Compound LE: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.30-7.39 (5H, m), 5.06(2H, s), 4.61 (1H, brs), 3.66 (2H, m), 3.12-3.17 (2H, m), 1.97 (2H, br),1.50-1.60 (2H, m), 1.45 (9H, s), 1.38 (3H, s); LC/MS (100%, t_(r)=2.500min), m/z=355 [M+Na]⁺ (Calc: 328).

A mixture of the compound of formula LE (2.48 g, 7.1 mmol) and 10%palladium on carbon (200 mg, Sigma-Aldrich) in methanol (20 mL) wasstirred under a hydrogen atmosphere at a temperature of about 25° C. for16 h. The Pd/C was filtered off and the filtrate was concentrated underreduced pressure to provide 1.37 g of the compound of formula LF as asilvery-colored viscous oil (yield 90.2%).

The identity of the compound of formula LF, tert-butyl4-amino-4-methylpiperidine-1-carboxylate, was confirmed using ¹H NMR.

Compound LF: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 3.47-3.49 (4H, m),1.47-1.61 (4H, m), 1.46 (9H, s), 1.31-1.42 (2H, m), 1.15 (3H, s).

A mixture of the compound of formula LF (1.37 g, 6.41 mmol), thecompound of formula LG (2-fluoro-1-nitrobenzene, 2.71 mL, 25.6 mmol,Sigma-Aldrich) and potassium carbonate (4.43 g, 32.1 mmol) in DMSO (110mL) was stirred at a temperature of 80° C. for 24 h. The mixture waspartitioned between EtOAc and water. The organic layer was separated,washed with brine, dried (Na₂SO₄), filtered, and concentrated to drynessunder reduced pressure. The residue was chromatographed (COMBIFLASH)with a gradient of from 0%:100% EtOAc:hexanes to 50%:50% EtOAc:hexanesto provide, after concentration under reduced pressure, 2.03 g of thecompound of formula LH as pale yellow oil (yield 94.4%).

The identity of the compound of formula LH, tert-butyl4-methyl-4-(2-nitrophenylamino)piperidine-1-carboxylate, was confirmedusing ¹H NMR and LC/MS.

Compound LH: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 8.41 (1H, br), 8.20 (1H,dd, J=8.6 Hz, 1.7 Hz), 7.36-7.40 (1H, m), 7.03 (1H, dd, J=8.8 Hz, 0.9Hz), 6.62-6.66 (1H, m), 3.77-3.79 (2H, m), 3.16-3.18 (2H, m), 2.10-2.13(2H, m), 1.67-1.74 (2H, m), 1.53 (3H, s), 1.46 (9H, s); LC/MS (100%,t_(r)=3.410 min), m/z=358.1 [M+Na]⁺ (Calc: 335).

To a mixture of the compound of formula LH (3.02 g, 9.00 mmol) in DCM (0mL) at a temperature of 0° C. was added 1N HCl in diethyl ether (30 mL,30 mmol). The mixture was allowed to warm to a temperature of about 25°C. for 20 h. The mixture was concentrated under reduced pressure toprovide a pale yellow solid. To a mixture of the solid and TEA (4.39 mL,31.5 mmol) in DCM (25 mL) at a temperature of 0° C. was addedtrifluoroacetic anhydride (TFFA, 1.40 mL, 9.90 mmol, Sigma-Aldrich).After being stirred at 0° C. for 45 min, 0.70 mL of additional TFFA wasadded to the mixture. The mixture was further stirred at 0° C. for 5 minafter which it was partitioned between DCM and water. The organic layerwas separated, washed with brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure to provide 2.80 g of the compound offormula L1 as an orange solid (yield 93.9%).

The identity of the compound of formulaL1,2,2,2-trifluoro-1-(4-methyl-4-(2-nitrophenylamino)piperidin-1-yl)ethanone,was confirmed using LC/MS.

Compound L1: LC/MS (100%, t_(r)=2.933 min), m/z=354.1 [M+Na]⁺ (Calc:331).

A mixture of the compound of formula L1 (1.50 g, 4.53 mmol) in neatcompound of formula LI (ethyl 2-chloro-2-oxoacetate, 10.1 mL, 90.6 mmol,Sigma-Aldrich) was stirred at a temperature of 65° C. for 3 h. Aftercooling to a temperature of about 25° C., the mixture was partitionedbetween EtOAc and water. The organic layer was separated, washed withbrine, dried (Na₂SO₄), filtered, and concentrated to dryness underreduced pressure. The residue was chromatographed (COMBIFLASH) with agradient of from 0%:100% EtOAc:hexanes to 50%:50% EtOAc:hexanes toprovide, after concentration under reduced pressure, 2.80 g of thecompound of formula LK as a yellow oil (yield 93.9%).

The identity of the compound of formula LK, ethyl2-((4-methyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)(2-nitrophenyl)no)-2-oxoacetate,was confirmed using ¹H NMR and LC/MS.

Compound LK: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 8.04 (1H, ddd, J=7.8 Hz,3.2 Hz, 1.8 Hz), 7.61-7.70 (2H, m), 7.39-7.43 (1H, m), 4.39 (2H, q,J=7.1 Hz), 3.87-3.96 (2H, m), 3.26-3.35 (1H, m), 2.88-2.98 (1H, m),2.49-2.53 (0.5H, m), 2.28-2.31 (0.5H, m), 1.95-2.19 (2H, m), 1.90-1.93(1H, m), 1.82 (1.5H, s), 1.77 (1.5H, m), 1.39 (3H, t, J=7.1 Hz); LC/MS(100%, t_(r)=2.833 min), m/z=454.1 [M+Na]⁺ (Calc: 431).

A mixture of the compound of formula LK (1.48 g, 3.43 mmol) and 10%palladium on carbon (150 mg) in EtOH (10 mL) was stirred under ahydrogen atmosphere at a temperature of about 25° C. for 4 h. The Pd/Cwas filtered off and the filtrate was concentrated to dryness underreduced pressure. The residue was chromatographed with a silica gelcolumn eluted with 0%-50% EtOAc:hexanes to provide, after concentrationunder reduced pressure, 723 mg of the compound of formula LL as a whitesolid (yield 52.5%).

The identity of the compound of formula LL,1-(4-methyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Compound LL: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 11.54 (1H, br), 7.64 (1H,d, J=8.1 Hz), 7.52 (1H, dd, J=8.1 Hz, 1.5 Hz), 7.27-7.30 (1H, m),7.16-7.20 (1H, m), 3.74-3.78 (1H, m), 3.56-3.59 (1H, m), 2.88-2.94 (1H,m), 2.71-2.81 (3H, m), 2.04-2.12 (2H, m), 1.80 (3H, s); LC/MS (100%,t_(r)=2.250 min), m/z=378.1 [M+Na]⁺ (Calc: 355).

To a mixture of the compound of formula LL (331 mg, 0.93 mmol) in EtOH(2 mL)/H₂O (0.5 mL) at a temperature of about 25° C. was added 21 wt. %sodium ethoxide in EtOH (0.38 mL, 1.03 mmol). The mixture was stirred ata temperature of about 25° C. for 16 h. The mixture was concentrated todryness under reduced pressure. The residue was washed with DCM toprovide a tan solid.

To a suspension of the solid in DMSO (3 mL) at a temperature of about25° C. was added the compound of formula AB (260 mg, 1.12 mmol). Afterbeing stirred at a temperature of about 25° C. for 1 h, TEA (0.16 mL,1.12 mmol) was added. The mixture was stirred an additional 3 h at atemperature of about 25° C. The mixture was partitioned between EtOAcand water. The organic layer was separated, washed with brine, dried(Na₂SO₄), filtered, and concentrated to dryness under reduced pressure.The residue was chromatographed with a silica gel column eluted with agradient of from 100%:0% MeOH:DCM to 20%:80% MeOH:DCM. Furtherchromatography was conducted with preparative TLC (eluted with agradient of from 0%:100% MeOH:DCM to 20%:80% MeOH:DCM) to provide 26.6mg of Heterocyclic-Substituted Piperidine Compound 62 as a white solid(yield 6.9%).

The identity of Heterocyclic-Substituted Piperidine Compound 62,1-(1-(1,2-dihydroacenaphthylen-1-yl)-4-methylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 62: ¹H NMR: δ_(H) (400 MHz,CD₃OD): 7.56 (1H, d, J=8.2 Hz), 7.45 (1H, d, J=8.2 Hz), 7.39 (1H, d,J=6.8 Hz), 7.37 (1H, d, J=6.8 Hz), 7.27-7.30 (1H, m), 7.18 (1H, d, J=6.8Hz), 7.11 (1H, d, J=6.8 Hz), 6.82-7.03 (3H, m), 4.66-4.67 (1H, m), 3.31(1H, dd, J=17.7 Hz, 8.0 Hz), 3.04-3.09 (1H, m), 2.83-2.92 (2H, m),2.31-2.34 (2H, m), 2.11 (1H, m), 1.69-1.77 (2H, m), 1.67 (3H, s), 1.42(1H, m); LC/MS (100%, t_(r)=4.64 min), m/z=412.2 [M+H]⁺ (Calc: 411).

5.23 Example 23

A mixture of the compound of formula L1 (797 mg, 2.41 mmol) and thecompound of formula MA (ethyl 3-chloro-3-oxopropanoate, 1.51 mL, 12.0mmol), in DCE (15 mL) was stirred at a temperature of 70° C. for 55 h.After cooling to a temperature of about 25° C., the mixture waspartitioned between DCM and water. The organic layer was separated,washed with brine, dried (MgSO₄), filtered, and concentrated to drynessunder reduced pressure. The residue was chromatographed with a silicagel column eluted with a gradient of from 0%:100% EtOAc:hexanes to50%:50% EtOAc:hexanes to provide, after concentration under reducedpressure, 659 mg of the compound of formula MB as a pale yellow oil(yield 61.5%).

The identity of the compound of formula MB, ethyl3-((4-methyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)(2-nitrophenyl)amino)-3-oxopropanoate,was confirmed using ¹H NMR and LC/MS.

Compound MB: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.85-7.89 (1H, m),7.60-7.68 (2H, m), 7.39-7.42 (1H, m), 4.31-4.38 (1H, m), 4.12 (2H, q,J=7.1 Hz), 4.07-4.16 (1H, m), 3.18-3.27 (2H, m), 3.02 (1H, dd, J=16.0Hz, 5.4 Hz), 2.85-2.88 (1H, m), 2.24-2.37 (1H, m), 2.05 (3H, s),1.64-1.95 (3H, m), 1.23 (3H, t, J=7.1 Hz); LC/MS (100%, t_(r)=2.787min), m/z=468.1 [M+Na]⁺ (Calc: 445).

A mixture of the compound of formula MB (659 mg, 1.59 mmol) and 10%palladium on carbon (60 mg) in EtOH (5 mL) was stirred under a hydrogenatmosphere at a temperature of about 25° C. for 3 h. The Pd/C wasfiltered off and the filtrate was concentrated under reduced pressure toprovide 572 mg of the compound of formula MC as a colorless oil (yield93.1%).

The identity of the compound of formula MC, ethyl3-((2-aminophenyl)(4-methyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)-3-oxopropanoate,was confirmed using LC/MS.

Compound MC: LC/MS (100%, t_(r)=2.898 min), m/z=438.1 [M+Na]⁺ (Calc:415).

To a mixture of the compound of formula MC (106 mg, 0.254 mmol) in EtOH(2 mL) at a temperature of about 25° C. was added pieces of sodium (20.4mg, 0.889 mmol). The mixture was stirred at a temperature of about 25°C. for 1 h, then stirred at a temperature of 70° C. for 1 h. Aftercooling to a temperature of about 25° C., the mixture was concentratedunder reduced pressure to provide an orange solid. A mixture of thesolid, the compound of formula AB (88.8 mg, 0.381 mmol), and TEA (0.078mL, 0.559 mmol) in DCE (2 mL) was stirred at a temperature of about 25°C. for 16 h. The mixture was partitioned between DCM and water. Theorganic layer was separated, washed with brine, dried (MgSO₄), filtered,and concentrated to dryness under reduced pressure. The residue waschromatographed by preparative TLC (eluted with a gradient of from0%:100% MeOH:DCM to 20%:80% MeOH:DCM) to provide 14.5 mg ofHeterocyclic-Substituted Piperidine Compound 63 as an off white solid(yield 13.4%).

The identity of Heterocyclic-Substituted Piperidine Compound 63,1-(1-(1,2-dihydroacenaphthylen-1-yl)-4-methylpiperidin-4-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 63: ¹H NMR: δ_(H) (400 MHz,CD₃OD): 7.65-7.69 (1H, m), 7.57-7.60 (1H, m), 7.37-7.52 (4H, m),7.15-7.36 (4H, m), 4.74-4.80 (1H, m), 3.39-3.49 (2H, m), 2.74-3.00 (2H,m), 2.43-2.47 (1H, m), 2.13-2.31 (1H, m), 1.57-1.96 (4H, m), 1.75 1(1.5H, s), 1.747 (1.5H, s); LC/MS (100%, t_(r)=2.064 min), m/z=426.1[M+H]⁺ (Calc: 425).

5.24 Example 24

To a mixture of the compound of formula MC (572 mg, 1.38 mmol) in EtOH(2 mL) at a temperature of about 25° C. was added pieces of sodium (111mg, 4.82 mmol). The mixture was stirred at a temperature of 70° C. for 3h. After cooling to a temperature of about 25° C., the mixture wasconcentrated under reduced pressure to provide a white solid.

A mixture of that solid, the compound of formula KH (252 mg, 1.33 mmol),potassium carbonate (368 mg, 2.66 mmol) and potassium iodide (23.8 mg,0.11 mmol) in acetonitrile (5 mL) was stirred at a temperature of 80° C.for 3 h. The mixture was partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried (Na₂SO₄),filtered, and concentrated to dryness under reduced pressure. Theresidue was chromatographed with a silica gel column eluted with agradient of from 0%:100% MeOH:DCM to 20%:80% MeOH:DCM to provide, afterconcentration under reduced pressure, 136 mg of Heterocyclic-SubstitutedPiperidine Compound 64 as a white solid (yield 32.0%).

The identity of Heterocyclic-Substituted Piperidine Compound 64,(Z)-1-(1-(Cyclooct-2-enyl)-4-methylpiperidin-4-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 64: ¹H NMR: δ_(H) (400 MHz,CD₃OD): 7.49-7.51 (1H, m), 7.36-7.41 (1H, m), 7.24-7.30 (2H, m),5.76-5.87 (1H, m), 5.30-5.39 (1H, m) 3.22-3.27 (1H, m), 2.81-2.99 (2H,brs), 2.68-2.69 (1H, m), 2.05-2.38 (5H, m), 1.59-1.95 (8H, m), 1.78 (3H,s), 1.21-1.51 (4H, m); LC/MS (100%, t_(r)=1.952 min), m/z=382.2 [M+H]⁺(Calc: 381).

Heterocyclic-Substituted Piperidine Compound 64 (76.7 mg, 0.20 mmol),10% palladium on carbon (20 mg) and concentrated HCl (0.05 mL) inmethanol (2 mL) was stirred under a hydrogen atmosphere at a temperatureof about 25° C. for 3 h. The Pd/C was filtered off and the filtrate wasconcentrated to dryness under reduced pressure. The residue waspartitioned between EtOAc and 1N aqueous NaOH. The organic layer waswashed with brine, dried (Na₂SO₄), filtered, and concentrated to drynessunder reduced pressure. The residue was triturated with hexanes toprovide 572 mg of Heterocyclic-Substituted Piperidine Compound 65 as awhite solid (yield 93.1%).

The identity of Heterocyclic-Substituted Piperidine Compound 65,1-(1-cyclooctyl-4-methylpiperidin-4-yl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 65: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 7.49 (1H, d, J=7.0 Hz), 7.38 (1H, td, J=7.7 Hz, 1.3 Hz),7.23-7.29 (2H, m), 2.79-3.14 (2H, brs), 2.50 (2H, m), 2.31-2.36 (1H, m),2.19-2.22 (1H, m), 1.44-1.91 (19H, m), 1.77 (3H, s); LC/MS (100%,t_(r)=1.972 min), m/z=384.2 [M+Na]⁺ (Calc: 383).

5.25 Example 25

A mixture of the compound of formula NA (3-nitropyridin-2-amine, 1.39 g,10 mmol), (BOC)₂O (20 mmol), and DMAP (catalytic amount) in THF (28 mL)was stirred at 90° C. for 1 h. After cooling to a temperature of about25° C. and quenching with water (10 mL), the mixture was extracted threetimes with EtOAc, dried (MgSO₄), and concentrated under reducedpressure. At a temperature of about 25° C., the resulting yellow oil wasmixed with methanol (33 mL) then added to K₂CO₃ (30 mmol). The reactionmixture was stirred at 60° C. for 1 h. After cooling to a temperature ofabout 25° C., 2N HCl (10 mL) was added and the pH was adjusted withinthe range of from about 7 to about 8. Thereafter, the mixture wasextracted three times with EtOAc, dried (MgSO₄), and concentrated underreduced pressure. The resulting oil was chromatographed with a silicagel column eluted with a gradient of from 10%:90% EtOAc:n-hexane to50%:50% EtOAc:n-hexane to provide the compound of formula NB as a yellowsolid (yield 91%).

The identity of the compound of formula NB, tert-butyl3-nitropyridin-2-ylcarbamate, was confirmed using ¹H NMR.

Compound NB: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 9.59 (1H, s), 8.72 (1H, dd,J=4.5 Hz, J=1.5 Hz), 8.5 (1H, dd, J=8.4 Hz, J=1.5 Hz), 7.14 (1H, dd,J=8.4 Hz, J=4.8 Hz), 1.56 (9H, s).

A mixture of the compound of formula NB (2.11 g, 9.07 mmol) and 5%palladium on carbon (210 mg, Sigma-Aldrich) in methanol (35 mL) wasstirred at a temperature of about 25° C. for 16 h in a hydrogenatmosphere. After the Pd/C was filtered off, the mixture was washed withEtOAc and methanol, and the filtrate was concentrated under reducedpressure. The resulting solid was suspended with 3:2 n-hexane:diethylether which was filtered and washed with n-hexane to provide thecompound of formula NC as a pale yellow solid (yield 87%).

The identity of the compound of formula NC, tert-butyl3-aminopyridin-2-ylcarbamate, was confirmed using ¹H NMR.

Compound NC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.76 (1H, d, J=1.5 Hz),7.10 (1H, dd, J=8.4 Hz, J=1.5 Hz), 6.99 (1H, dd, J=8.4 Hz, J=4.8 Hz),1.52 (9H, s).

A mixture of the compound of formula NC (710 mg, 3.4 mmol), the compoundof formula BA (5.1 mmol), NaBH(OAc)₃ (10.2 mmol) and AcOH (5.1 mmol) inchloroform (18 mL) was stirred at a temperature of about 25° C. for 16h. After quenching with saturated NaHCO₃ solution, the mixture wasextracted with chloroform, dried (MgSO₄), and concentrated under reducedpressure. The residue was chromatographed with an amino-silica gelcolumn (Yamazen Corp. W091-01) eluted with a gradient of from 5%:95%EtOAc:n-hexane to 20%:80% EtOAc:n-hexane to 50%:50% EtOAc:n-hexane toprovide the compound of formula ND as a colorless solid (yield 63%).

The identity of the compound of formula ND, tert-butyl3-(1-cyclooctylpiperidin-4-ylamino)pyridin-2-ylcarbamate, was confirmedusing ¹H NMR.

Compound ND: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 8.59 (1H, s), 7.60 (1H,t, J=4 Hz), 7.01 (2H, d), 4.67 (1H, d, J=8 Hz), 3.25 (1H, m), 2.67 (2H,m), 2.35-2.30 (2H, m), 1.88-1.85 (2H, m), 1.69-1.60 (2H, m), 1.56-1.32(25H, m).

To a suspension of the compound of formula ND (317 mg, 0.79 mmol) inEtOAc (5 mL) at a temperature of about 25° C. was added 4N HCl in EtOAc(7.9 mmol) which was stirred at about 25° C. for 1 h and then for 3 hmore at 50° C. After neutralization with 28% aqueous ammonia, the pH wasadjusted within the range of from about 13 to about 14. Thereafter, themixture was extracted three times with EtOAc, the organic layer wasdried (MgSO₄), and concentrated under reduced pressure to provide 237 mgof the compound of formula NE as a brown solid (yield >99%).

The identity of the compound of formula NEN³-(1-cyclooctylpiperidin-4-yl)pyridine-2,3-diamine, was confirmed using¹H NMR.

Compound NE: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.80 (1H, d, J=4 Hz), 7.66(1H, s), 6.39 (1H, d, J=4 Hz), 4.12 (1H, m), 2.79 (1H, m), 2.68-2.61(6H, m), 2.43 (2H, m), 1.92-1.48 (24H, m).

To a mixture of the compound of formula NE (168 mg, 0.79 mmol) inmethylene chloride (10 mL) at 0° C. was added dropwise over 10 minmethyl 2-chloro-2-oxoacetate (0.79 mmol) in methylene chloride (3 mL).The resulting reaction mixture was stirred at 0° C. for 30 min. Afterquenching with saturated NaHCO₃ solution, the mixture was extractedthree times with chloroform. Thereafter, the organic layer was dried(MgSO₄) and concentrated under reduced pressure. At a temperature ofabout 25° C., the resulting oil was mixed with EtOH (4 mL) and themixture was then added to sodium methoxide (1.09 mmol). The reactionmixture was stirred at 70° C. for 1 h. After concentration under reducedpressure, to the resulting oil was added water (0.5 mL) and 2N HCl (1mL). The resulting precipitate was filtered, washed with 90%:10%water:MeOH, and dried under reduced pressure at 60° C. for 12 h toprovide the dihydrochloride of Heterocyclic-Substituted PiperidineCompound 66 as a colorless solid.

The identity of Heterocyclic-Substituted Piperidine Compound 66,1-(1-cyclooctylpiperidin-4-yl)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 66: ¹H NMR: δ_(H) (300 MHz,DMSO-d₆): 12.39 (1H, s), 9.8 (1H, br), 8.27 (1H, m), 8.14 (1H, d, J=4.5Hz), 7.21 (1H, dd, J=4.5 Hz, J=8.1 Hz), 4.91 (1H, m), 3.45-3.3 (6H, m),2.99 (2H, m), 2.02 (2H, m), 1.99 (2H, m), 1.58-1.46 (11H, m); LC/MS,m/z=357 [M+H]⁺ (Calc: 356.5).

To a mixture of the compound of formula NE (302 mg, 1 mmol) in methylenechloride (30 mL) at 0° C. was added dropwise over 2 h malonyl dichloride(1.5 mmol) in methylene chloride (30 mL). Thereafter, the resultingreaction mixture was stirred at a temperature of about 25° C. for 3days. After concentration under reduced pressure, the resulting oil waschromatographed with a silica gel column eluted with a gradient of from97%:3%:0.3% chloroform:MeOH:28% aqueous ammonia to 90%:10%:0.1%chloroform:MeOH:28% aqueous ammonia to provide a yellow amorphous solid.The solid was mixed with 1:1 EtOAc:MeOH (2 mL) and added to 4N HCl inEtOAc (0.5 mL) at a temperature of about 25° C. to provide a whiteprecipitate. The precipitate was filtered and washed with 9:1 diethylether:MeOH. The resulting colorless solid was dried under reducedpressure at 60° C. for 12 h to provide 60 mg of the dihydrochloride ofHeterocyclic-Substituted Piperidine Compound 667 (yield 14%).

The identity of Heterocyclic-Substituted Piperidine Compound 67,1-(1-cyclooctylpiperidin-4-yl)-1H-pyrido[3,2-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 67: ¹H NMR: δ_(H) (300 MHz,CD₃OD): 8.36 (1H, dd, J=1.5 Hz, J=4.8 Hz), 7.97 (1H, dd, J=8.1 Hz, J=1.5Hz), 7.37 (1H, dd, J=8.1 Hz, J=4.8 Hz), 4.23 (1H, m), 3.53-3.42 (4H, m),3.27-3.13 (3H, m), 2.78 (2H, m), 2.14-1.54 (16H, m); LC/MS, m/z=371.0[M+H]⁺ (Calc: 370.4).

5.26 Example 26

At 0° C., 4-methoxybenzoyl chloride (3.03 g, 17.8 mmol, Sigma-Aldrich)in 10 mL of dry methylene chloride was added dropwise to a mixture ofthe compound of formula BB (5.37 g, 17.8 mmol), TEA (2.48 mL, 17.8mmol), and 53 mL of dry methylene chloride. The reaction mixture wasstirred at 0° C. for 1 h. After concentration under reduced pressure,the resulting solid was filtered and washed with methylene chloride.After drying under reduced pressure, 8 g of the compound of formula OAwas obtained.

The identity of the compound of formula OA,N-(2-(1-cyclooctylpiperidin-4-ylamino)phenyl)-4-methoxybenzamide, wasconfirmed using ¹H NMR.

Compound OA: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 9.61 (1H, s), 7.97 (2H,d, J=8.8 Hz), 7.18 (1H, m), 7.11 (1H, m), 7.04 (2H, d, J=8.0 Hz), 6.80(1H, m), 6.66 (1H, m), 4.88 (1H, m), 3.83 (3H, s), 3.57 (1H, m),3.10-3.33 (4H, cm), 1.89-2.20 (5H, cm), 1.46-1.87 (14H, cm).

A slurry of the compound of formula OA in 100 mL of dry THF was added toa stirred solution of lithium aluminum hydride (LiAlH₄, 1.43 g, 37.6mmol, Sigma-Aldrich) in 501 mL of dry THF at 0° C., then heated toreflux for 3 h. Thereafter, the reaction mixture was cooled to atemperature of about 25° C. and water (1.43 mL), 2N aqueous NaOH (1.43mL), water (4.29 mL), and chloroform were added in that order. Afterfiltering the resulting mixture through a pad of CELITE, the filtratewas extracted with chloroform. The organic layer was dried (Na₂SO₄),filtered, and concentrated to dryness under reduced pressure to provide7.2 g of the compound of formula OB.

The identity of the compound of formula OB,N¹-(1-cyclooctylpiperidin-4-yl)-N²-(4-methoxybenzyl)benzene-1,2-diamine,was confirmed using ¹H NMR.

Compound OB: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 7.27 (2H, d, J=8.4 Hz),6.87 (2H, d, J=8.4 Hz), 6.48 (2H, m), 6.42 (1H, m), 6.39 (1H, m), 5.15(1H, t, J=5.2 Hz), 4.28 (1H, d, J=6.8 Hz), 4.19 (2H, d, J=5.2 Hz), 3.72(3H, s), 3.13 (1H, m), 2.73 (2H, m), 2.55 (1H, m), 2.27 (2H, m), 1.93(2H, m), 1.31-1.70 (16H, cm).

To a mixture of the compound of formula OB (3.4 g, 8.08 mmol) and 60 mLof THF was added ethyl isocyanatidocarbonate (1.48 mL, 12.11 mmol,Sigma-Aldrich). The mixture was sealed in a microwave reaction vesseland warmed to 150° C. with microwave irradiation and stirring for 45min. Thereafter, the reaction mixture was concentrated to dryness underreduced pressure. The resulting solid was filtered then washed withethyl acetate. After drying under reduced pressure, 2.9 g ofHeterocyclic-Substituted Piperidine Compound 68 was obtained (yield73%).

The identity of Heterocyclic-Substituted Piperidine Compound 68,1-(1-cyclooctylpiperidin-4-yl)-5-(4-methoxybenzyl)-1H-benzo[f][1,3,5]triazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 68: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 8.79 (1H, s), 7.49 (1H, m), 7.31 (1H, m), 7.25 (2H, m), 7.11(2H, d, J=8.4 Hz), 6.79 (2H, d, J=8.4 Hz), 5.20 (1H, d, J=20 Hz), 4.73(1H, d, J=20 Hz), 3.66 (3H, s), 3.53 (1H, m), 2.75 (1H, m), 2.64 (1H,m), 2.17 (2H, m), 2.05-1.70 (3H, cm), 1.31-1.70 (16H, cm); LC/MS (100%,t_(r)=2.79 min), m/z=490.9 [M+H]⁺ (Calc: 490.0).

Heterocyclic-Substituted Piperidine Compound 68 (500 mg, 1.02 mol) in 5mL of DMF was added dropwise to a suspension of NaH (61 mg, 1.53 mmol,Sigma-Aldrich) in 2 mL of DMF at 0° C. Thereafter, the reaction mixturewas stirred at a temperature of about 25° C. for 1 h. Then, benzyl2-bromoacetate (193 μL, 1.22 mmol, TCI America) was added to thereaction mixture at 0° C. followed by stirring at a temperature of about25° C. for 3 h. Water was then added to the reaction mixture followed byextraction with EtOAc. The organic layer was washed with water, dried(Na₂SO₄), filtered, and concentrated to dryness under reduced pressureto provide 844 mg of Heterocyclic-Substituted Piperidine Compound 69,benzyl2-(1-(1-cyclooctylpiperidin-4-yl)-5-(4-methoxybenzyl)-2,4-dioxo-4,5-dihydro-1H-benzo[f][1,3,5]triazepin-3(2H)-yl)acetate.

A mixture of Heterocyclic-Substituted Piperidine Compound 69 (844 mg),10% palladium on carbon (254 mg, N.E. Chemcat, Tokyo, Japan), andmethanol (20 mL) was stirred under a hydrogen atmosphere at atemperature of about 25° C. for 2 h. After the Pd/C was filtered off,the remaining material was washed with methanol and DMF and the filtratewas concentrated under reduced pressure to provide a solid. Theresulting solid was washed with EtOAc to provide 500 mg ofHeterocyclic-Substituted Piperidine Compound 70 as a gray solid (yield89% for two steps).

The identity of Heterocyclic-Substituted Piperidine Compound 70,2-(1-(1-cyclooctylpiperidin-4-yl)-5-(4-methoxybenzyl)-2,4-dioxo-4,5-dihydro-1H-benzo[f][1,3,5]triazepin-3(2H)-yl)aceticacid, was confirmed using MS.

Heterocyclic-Substituted Piperidine Compound 70: MS, m/z=549.1 [M+H]⁺(Calc: 548).

To a mixture of Heterocyclic-Substituted Piperidine Compound 70 (100 mg,0.182 mmol), HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V), 83.3 mg, 0.219 mmol, Peptide Institute/PeptidesInternational, Louisville, Ky.), triethylamine (50.7 μL, 0.364 mmol) andDMF (10 L) was added methanamine (as a 2M THF solution, 109 μL, 0.219mmol, Sigma-Aldrich). The reaction mixture was stirred at a temperatureof about 25° C. for 2 h. Water was then added to the reaction mixturefollowed by extraction with EtOAc. The organic layer was washed withwater, dried (Na₂SO₄), filtered, and concentrated to dryness underreduced pressure to provide the Heterocyclic-Substituted PiperidineCompound 71,2-(1-(1-cyclooctylpiperidin-4-yl)-5-(4-methoxybenzyl)-2,4-dioxo-4,5-dihydro-1H-benzo[f][1,3,5]triazepin-3(2H)-yl)-N-methylacetamide.

At a temperature of about 25° C., ceric ammonium nitrate (CAN, 559 mg,1.02 mmol, Nacalai Tesque, Koyoto, Japan) was added portionwise over a10 min period to a stirred mixture of the quantity ofHeterocyclic-Substituted Piperidine Compound 71 prepared above andacetonitrile:water (4.5 mL:0.5 mL). Then, the reaction mixture wasstirred at 50° C. for 5 h. Thereafter, the mixture was cooled to atemperature of about 25° C., saturated aqueous NaHCO₃ was added, and themixture was extracted with chloroform. The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas chromatographed with a silica gel column eluted with a gradient offrom 0%:100% CHCl₃:MeOH to 80%:20% CHCl₃:MeOH. The product fractionswere combined and concentrated to dryness under reduced pressure toprovide 21.7 mg of Heterocyclic-Substituted Piperidine Compound 72(yield 27% for two steps).

The identity of Heterocyclic-Substituted Piperidine Compound 72,2-(1-(1-cyclooctylpiperidin-4-yl)-2,4-dioxo-4,5-dihydro-1H-benzo[f][1,3,5]triazepin-3(2H)-yl)-N-methylacetamide,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 72: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 9.80 (1H, s), 7.77 (1H, m), 7.36 (1H, m), 7.24 (2H, m), 7.11(1H, m), 3.93 (2H, s), 3.68 (1H, m), 2.73 (2H, m), 2.51 (3H, s), 2.20(2H, m), 2.05 (1H, m), 1.97 (2H, m), 1.31-1.70 (16H, cm); LC/MS (100%,t_(r)=1.87 min), m/z=456.1 [M+H]⁺ (Calc: 455).

Heterocyclic-Substituted Piperidine Compounds 73, 74 and 75 wereprepared from the compound of formula L2 as described above except thatdimethylamine, pyridin-3-amine, or morpholine, respectively, was used inplace of methanamine.

The identity of Heterocyclic-Substituted Piperidine Compound 73,2-(1-(1-cyclooctylpiperidin-4-yl)-2,4-dioxo-4,5-dihydro-1H-benzo[f][1,3,5]triazepin-3(2H)-yl)-N,N-dimethylacetamide,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 73: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 9.80 (1H, s), 7.36 (1H, m), 7.21 (2H, m), 7.13 (1H, m), 4.21(2H, s), 3.74 (1H, m), 2.93 (3H, s), 2.80 (2H, m), 2.73 (3H, s), 2.31(1H, m), 2.11 (1H, m), 1.99 (2H, m), 1.31-1.70 (16H, cm); LC/MS (100%,t_(r)=1.66 min), m/z=442.08 [M+H]⁺ (Calc: 441).

The identity of Heterocyclic-Substituted Piperidine Compound 74,2-(1-(1-cyclooctylpiperidin-4-yl)-2,4-dioxo-4,5-dihydro-1H-benzo[f][1,3,5]triazepin-3(2H)-yl)-N-(pyridin-3-yl)acetamide,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 74: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 10.34 (1H, brs), 9.96 (1H, s), 8.66 (1H, m), 8.24 (1H, m),7.95 (1H, m), 7.42 (1H, m), 7.26 (3H, m), 7.16 (1H, m), 4.22 (2H, s),3.75 (1H, m), 2.74 (2H, m), 1.99 (1H, m), 1.31-1.88 (20H, cm); LC/MS(100%, t_(r)=1.27 min), m/z=505.0 [M+H]⁺ (Calc: 504).

The identity of Heterocyclic-Substituted Piperidine Compound 75,1-(1-cyclooctylpiperidin-4-yl)-3-(2-morpholino-2-oxoethyl)-1H-benzo[/][1,3,5]triazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 75: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 10.25 (1H, brs), 9.89 (1H, s), 7.47 (1H, m), 7.21 (3H, m),4.26 (2H, s), 4.14 (1H, m), 3.50 (4H, m), 3.36 (4H, m), 3.14 (2H, m),2.66 (1H, m), 2.17 (1H, m), 1.99 (2H, m), 1.31-1.70 (16H, cm); LC/MS(100%, t_(r)=1.77 min), m/z=497.8 [M+H]⁺ (Calc: 497).

5.27 Example 27

Heterocyclic-Substituted Piperidine Compound 68 (200 mg, 0.408 mol) in 3mL of DMF was added dropwise to a suspension of NaH (48 mg, 1.224 mmol)in 1 mL of DMF at 0° C., and the mixture was stirred at a temperature ofabout 25° C. for 1 h. After cooling the reaction mixture to 0° C.,2-(diethylamino)ethyl bromide hydrobromide (256 mg, 0.980 mmol,Sigma-Aldrich) and TEA (136 μL, 0.980 mmol) were added. The resultingmixture was heated to 50° C. and remained at that temperature for 3 h.The reaction mixture was cooled to a temperature of about 25° C., waterwas added, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water, dried (Na₂SO₄), filtered, and concentratedto dryness under reduced pressure to provide 275 mg ofHeterocyclic-Substituted Piperidine Compound 76,1-(1-cyclooctylpiperidin-4-yl)-3-(2-(diethylamino)ethyl)-5-(4-methoxybenzyl)-H-benzo[f][1,3,5]triazepine-2,4(3H,5H)-dione.

Using ceric ammonium nitrate, Heterocyclic-Substituted PiperidineCompound 77 was prepared as described in Example 26 except thatHeterocyclic-Substituted Piperidine Compound 76 was used in place ofHeterocyclic-Substituted Piperidine Compound 71. After concentrating todryness under reduced pressure, the residue was mixed with 2 mL of ethylacetate. To this was added 1 mL of 4M HCl in ethyl acetate. After againconcentrating to dryness under reduced pressure, the resulting residuewas triturated with methanol, filtered, and dried under reduced pressureto provide 79 mg of the dihydrochloride of Heterocyclic-SubstitutedPiperidine Compound 77 (yield 36% for two steps).

The identity of Heterocyclic-Substituted Piperidine Compound 77,1-(1-cyclooctylpiperidin-4-yl)-3-(2-(diethylamino)ethyl)-1H-benzo[f][1,3,5]triazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 77: ¹H NMR: δ_(H) (400 MHz,DMSO-d₆): 10.63 (1H, brs), 10.48 (1H, brs), 10.16 (1H, s), 7.49 (1H, m),7.31 (1H, m), 7.20 (2H, m), 4.19 (1H, m), 3.73 (2H, m), 3.35 (2H, m),3.14 (4H, m), 2.97 (4H, m), 2.70 (1H, m), 2.26 (1H, m), 1.98 (2H, m),1.31-1.70 (15H, cm), 0.97-1.16 (6H, m); LC/MS (100%, t_(r)=2.08 min),m/z=470.0 [M+H]⁺ (Calc: 469.0).

5.28 Example 28

From the sodium salt of Heterocyclic-Substituted Piperidine Compound 50,the synthesis of which is described in Example 18, the carboxylic acidhydrochloride was prepared. To a mixture of the hydrochloride ofHeterocyclic-Substituted Piperidine Compound 50 (200 mg, 0.46 mmol) anddry DMF (5 mL) was added 1-hydroxybenzotriazole (94.6 mg, 0.70 mmol,Sigma-Aldrich) and N-ethyl-dimethylaminopropyl carbodiimidehydrochloride (108.6 mg, 0.70 mmol, Sigma-Aldrich). Thereafter,piperidine (0.069 mL, 0.70 mmol) and DIEA (0.244 mL, 1.38 mmol) wereadded and the reaction mixture was stirred at a temperature of about 25°C. for 18 h. The mixture was partitioned between an aqueous potassiumcarbonate solution (100 mL) and ethyl acetate (100 mL). The organicphase was separated, dried (MgSO₄), and concentrated to dryness underreduced pressure to provide a yellow gum that was chromatographed byflash silica eluted with 200:10:1 EtOAc:MeOH:ammonia to provide 28 mg ofHeterocyclic-Substituted Piperidine Compound 78 as a as a white solid.

The identity of Heterocyclic-Substituted Piperidine Compound 78,1-(1-cyclooctyl-5-(piperidine-1-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR and TLC.

Heterocyclic-Substituted Piperidine Compound 78: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 11.9 (1H, s), 6.95 (3H, m), 6.85 (1H, m), 3.10-2.85 (5H, m), 2.6(3H, m), 2.20 (1H, m), 1.90 (1H, m), 1.65-1.10 (21H, m); TLC (SiO₂)200:10:1 EtOAc:MeOH:ammonia: Rf=0.38 with UV detection, Dragendorffsreagent.

Heterocyclic-Substituted Piperidine Compound 79 was prepared in a mannersimilar to that described above except that morpholine was used in placeof piperidine.

The identity of Heterocyclic-Substituted Piperidine Compound 79,1-(1-cyclooctyl-5-(morpholine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)quinoxaline-2,3(1H,4H)-dione,was confirmed using ¹H NMR.

Heterocyclic-Substituted Piperidine Compound 79: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 12.1 (1H, s), 7.15 (3H, m), 7.00 (1H, m), 3.60-3.35 (4H, m),3.15 (1H, m), 3.00 (1H, m), 2.78 (3H, m), 2.30 (1H, m), 2.10 (1H, m),1.80-1.39 (14H, m).

Heterocyclic-Substituted Piperidine Compound 80 was prepared in a mannersimilar to that described above except that benzylamine (Sigma-Aldrich)was used in place of piperidine.

The identity of Heterocyclic-Substituted Piperidine Compound 80,N-benzyl-1-cyclooctyl-4-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-1,2,5,6-tetrahydropyridine-3-carboxamide,was confirmed using ¹H NMR and TLC.

Heterocyclic-Substituted Piperidine Compound 80: ¹H NMR: δ_(H) (400 MHz,CDCl₃): 8.08 (1H, t, J=6.1 Hz), 7.20-7.06 (6H, m), 7.01 (1H, d, J=8.9Hz), 6.81 (1H, d, J=8.9 Hz), 4.10 (2H, ddd, J=16.7, 6.1 Hz), 2.77 (3H,m), 2.37 (1H, m), 2.15 (1H, m), 1.84-1.46 (14H, m); TLC (SiO₂) 40:10:1EtOAc:MeOH:ammonia: Rf=0.14 with UV detection, Dragendorffs reagent.

5.29 Example 29

In 200 mL of methanol, the compound of formula PA,6-methoxy-3-nitropyridin-2-amine (3.45 g, 20.0 mmol, Sigma-Aldrich) wassuspended. To this, 10% palladium on carbon (350 mg) was added and thereaction mixture was stirred for 6 h under a hydrogen atmosphere at atemperature of about 25° C. The mixture was filtered through CELITE andconcentrated to dryness under reduced pressure to provide 2.78 g of thecompound of formula PB as a violet solid (yield >99%).

The identity of the compound of formula PB,6-methoxypyridine-2,3-diamine, was confirmed using ¹H NMR.

Compound PB: ¹H NMR: δ_(H) (CDCl₃): 6.93 (1H, d, J=8.1 Hz), 6.04 (1H, d,J=8.1 Hz), 3.80 (3H, s).

The compound of formula PB (417 mg, 3.0 mmol) and1-(2,2,2-trifluoroacetyl)piperidin-4-one (702 mg, 3.6 mmol,Sigma-Aldrich) were suspended in 30 mL of dry chloroform. To this,sodium triacetoxyborohydride (1.27 g, 6.0 mmol) was added and thereaction mixture was stirred for 3 h at a temperature of about 25° C.Then, the mixture was poured into aqueous NaHCO₃ (20 mL) and extractedtwice with chloroform (30 mL for each extraction). The extracts werecombined, dried (MgSO₄), and concentrated to dryness under reducedpressure. The residue was chromatographed with a silica gel columneluted with a gradient of from 20%:80% EtOAc:n-hexane to 60%:40%EtOAc:n-hexane to provide 668 mg of the compound of formula PC as aviolet solid (yield 70%).

The identity of the compound of formula PC,1-(4-(2-amino-6-methoxypyridin-3-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone,was confirmed using ¹H NMR.

Compound PC: ¹H NMR: δ_(H) (CDCl₃): 7.01 (1H, d, J=8.1 Hz), 6.06 (1H, d,J=8.1 Hz), 4.50 (1H, brs), 4.35-4.40 (1H, m), 3.94-3.99 (1H, m), 3.82(3H, s), 3.19-3.36 (2H, m), 3.00-3.10 (1H, m), 2.04 (2H, m), 1.39-1.53(2H, m).

A mixture of the compound of formula PC (646 mg, 2.0 mmol) and 200 mL ofdry dichloromethane was added dropwise to a mixture of malonyldichloride (571 mg, 4.0 mmol) and 200 mL of dry dichloromethane. Theresulting reaction mixture was stirred for 3 h under a nitrogenatmosphere at 0° C. The mixture was allowed to warm to a temperature ofabout 25° C. for 20 h. Then, the reaction mixture was poured intoaqueous NaHCO₃ (300 mL) and extracted twice with chloroform (200 mL foreach extraction). The extracts were combined, dried (MgSO₄), andconcentrated to dryness under reduced pressure. The residue waschromatographed with a silica gel column eluted with a gradient of from70%:30% EtOAc:n-hexane to 100%:0% EtOAc:n-hexane to provide 548 mg ofthe compound of formula PD as a colorless solid (yield 70%).

The identity of the compound of formula PD,7-methoxy-1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-pyrido[3,2-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR.

Compound PD: ¹H NMR: δ_(H) (CDCl₃): 7.73 (1H, s), 7.50 (1H, dd, J=10.4,9.1 Hz), 6.66 (1H, d, J=9.1 Hz), 4.71-4.44 (2H, m), 4.15-4.01 (1H, m),3.92 (3H, s), 3.43 (1H, d, J=12.7 Hz), 3.32 (1H, d, J=12.7 Hz),3.22-3.16 (1H, m), 2.84-2.78 (1H, m), 2.29-2.26 (1H, m), 2.02-1.97 (1H,m), 1.69-1.62 (2H, m).

Potassium carbonate (1.00 g, 7.24 mmol) was added to a mixture of thecompound of formula PD (700 mg, 1.81 mmol) and 20 mL of methanol and thereaction mixture was stirred for 5 h at a temperature of about 25° C.Thereafter, the mixture was concentrated to dryness under reducedpressure and the resulting solid was suspended in 20 mL of acetonitrile.To this, the compound of formula KH (855 mg, 4.52 mmol) and potassiumiodide (30 mg, 0.181 mmol) were added and the reaction mixture wasrefluxed for 6 h. Then, the reaction mixture was poured into water (30mL) and extracted twice with chloroform (50 mL for each extraction). Theextracts were combined, dried (MgSO₄), and concentrated to dryness underreduced pressure. The residue was chromatographed with an amino-silicagel column eluted with a gradient of from 70%:30% EtOAc:n-hexane to100%:0% EtOAc:n-hexane to provide 548 mg of Heterocyclic-SubstitutedPiperidine Compound 81 as a pale yellow solid (yield 70%).

The identity of Heterocyclic-Substituted Piperidine Compound 81,(Z)-1-(1-(Cyclooct-2-enyl)piperidin-4-yl)-7-methoxy-1H-pyrido[3,2-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 81: ¹H NMR: δ_(H)(DMSO-d₆): 10.59 (1H, s), 7.81 (1H, dd, J=8.6, 1.8 Hz), 6.72 (1H, d,J=8.6 Hz), 5.67-5.65 (1H, m), 5.46-5.43 (1H, m), 3.98-3.95 (1H, m), 3.86(3H, s), 3.49 (1H, d, J=12.2 Hz), 3.27-3.24 (1H, m), 2.94-2.89 (3H, m),2.20-1.21 (16H, m); LC/MS (100%, t_(r)=1.72 min), m/z=399.0 [M+H]⁺(Calc: 398.2).

A mixture of Heterocyclic-Substituted Piperidine Compound 81 (434 mg,1.09 mmol), 20% Pd(OH)₂ on carbon (90 mg, Sigma-Aldrich), and methanol(25 mL) was stirred at a temperature of about 25° C. for 14 h in ahydrogen atmosphere. After filtration through CELITE, the filtrate wasconcentrated under reduced pressure to provide 425 mg ofHeterocyclic-Substituted Piperidine Compound 82 as a pale yellow solid(yield 97%).

The identity of Heterocyclic-Substituted Piperidine Compound 82,1-(1-cyclooctylpiperidin-4-yl)-7-methoxy-1H-pyrido[3,2-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 82: ¹H NMR: δ_(H)(DMSO-d₆): 10.59 (1H, s), 7.80 (1H, d, J=8.6 Hz), 6.72 (1H, d, J=8.6Hz), 3.94 (1H, m), 3.86 (3H, s), 3.49 (1H, d, J=12.7 Hz), 2.93 (1H, d,J=12.7 Hz), 2.73 (2H, m), 2.21 (2H, m), 2.01-1.85 (2H, m), 1.64-1.29(17H, m); LC/MS (100%, t_(r)=1.66 min), m/z=401.1 [M+H]⁺ (Calc: 400.3).

5.30 Example 30

A mixture of the compound of formula PB (2.00 g, 14.3 mmol), DIEA (2.96mL, 17.2 mmol), and 70 mL of dry dichloromethane was cooled to 0° C.under a nitrogen atmosphere. To this, a mixture of benzylcarbonochloridate (2.70 g, 15.8 mL, Sigma-Aldrich) and 70 mL of drydichloromethane was added and the reaction mixture was stirred for 1 hat 0° C. Then, the mixture was poured into aqueous NaHCO₃ (100 mL) andextracted twice with chloroform (100 mL for each extraction). Theextracts were combined, dried (MgSO₄), and concentrated to dryness underreduced pressure. The residue was chromatographed with a silica gelcolumn eluted with a gradient of from 35%:65% EtOAc:n-hexane to 55%:45%EtOAc:n-hexane to provide 3.26 g of the compound of formula QA as aviolet solid (yield 83%).

The identity of the compound of formula OA, benzyl2-amino-6-methoxypyridin-3-ylcarbamate, was confirmed using ¹H NMR.

Compound OA: ¹H NMR: δ_(H) (CDCl₃): 7.38 (6H, s), 6.10-6.06 (2H, m),5.18 (2H, s), 4.52 (2H, bs), 3.83 (3H, s).

The compound of formula OB was prepared from1-(2,2,2-trifluoroacetyl)piperidin-4-one in a manner similar to Example29 except that the compound of formula QA was used in place of thecompound of formula PB.

The identity of the compound of formula OB, benzyl6-methoxy-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-ylamino)pyridin-3-ylcarbamate,was confirmed using ¹H NMR.

Compound OB: ¹H NMR: δ_(H) (CDCl₃): 7.37 (5H, s), 7.24 (1H, d, J=8.1Hz), 6.03 (1H, d, J=8.1 Hz), 5.92 (1H, s), 5.17 (2H, s), 4.54 (1H, s),4.32-4.29 (1H, m), 4.19-4.11 (1H, m), 3.93-3.90 (1H, m), 3.85 (3H, s),3.32-3.29 (1H, m), 3.09-3.06 (1H, m), 2.17-2.09 (2H, m), 1.46-1.43 (2H,m).

The compound of formula OC was prepared from ethyl3-chloro-3-oxopropanoate in a manner similar to Example 16 except thatthe compound of formula QB was used in place of the compound of formulaGA.

The identity of the compound of formula QC, ethyl3-((3-(benzyloxycarbonylamino)-6-methoxypyridin-2-yl)(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)-3-oxopropanoate,was confirmed using ¹H NMR.

Compound OC: ¹H NMR: δ_(H) (CDCl₃): 8.26-8.24 (1H, m), 7.38-7.30 (6H,m), 6.85 (1H, d, J=8.6 Hz), 5.24-5.15 (2H, m), 4.65-4.43 (2H, m),4.15-3.97 (3H, m), 3.83-3.82 (3H, m), 3.17-3.03 (3H, m), 2.78-2.66 (1H,m), 2.18-2.12 (1H, m), 1.79-1.70 (2H, m), 1.26-1.19 (4H, m).

The compound of formula OC (188 mg, 0.332 mmol), 10% palladium on carbon(20 mg), and 10 mL of methanol were stirred for 1 h under a hydrogenatmosphere at a temperature of about 25° C. The reaction mixture wasfiltered through CELITE and concentrated to dryness under reducedpressure to provide 143 mg of the compound of formula OD as a colorlessamorphous solid (yield >99%).

The identity of the compound of formula OD, ethyl3-((3-amino-6-methoxypyridin-2-yl)(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)-3-oxopropanoate,was confirmed using ¹H NMR.

Compound QD: ¹H NMR: δ_(H) (CDCl₃): 7.12 (1H, d, J=8.6 Hz), 6.69 (1H, d,J=8.6 Hz), 4.76-4.69 (1H, m), 4.61-4.52 (1H, m), 4.13 (2H, q, J=7.1 Hz),4.01 (1H, m), 3.78 (3H, d, J=8.1 Hz), 3.62 (2H, bs), 3.22-3.16 (3H, m),2.84-2.77 (1H, m), 2.28-2.18 (1H, m), 2.07-1.80 (2H, m), 1.41-1.29 (1H,m), 1.23 (3H, t, J=7.1 Hz).

The compound of formula OE was prepared in a manner similar to Example14 except that the compound of formula OD was used in place of thecompound of formula FG and sodium ethoxide (Sigma-Aldrich) was used inplace of sodium methoxide.

The identity of the compound of formula OE,7-methoxy-5-(piperidin-4-yl)-1H-pyrido[2,3-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR.

Compound OE: ¹H NMR: δ_(H) (CDCl₃): 7.40 (1H, d, J=8.6 Hz), 6.69 (1H, d,J=8.6 Hz), 4.54 (1H, m), 3.97 (3H, s), 3.33 (2H, m), 3.15 (2H, m),2.73-2.58 (3H, m), 1.99 (2H, m), 1.53-1.44 (2H, m).

Heterocyclic-Substituted Piperidine Compound 83 was prepared from thecompound of formula KH in a manner similar to Example 29 except that thecompound of formula OE was used in place of the compound of formula PD.

The identity of Heterocyclic-Substituted Piperidine Compound 83,(Z)-5-(1-(Cyclooct-2-enyl)piperidin-4-yl)-7-methoxy-1H-pyrido[2,3-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 83: ¹H NMR: δ_(H)(DMSO-d₆): 10.22 (1H, s), 7.51 (1H, d, J=8.6 Hz), 6.80 (1H, d, J=8.6Hz), 5.66 (1H, m), 5.49 (1H, m), 4.25 (1H, m), 3.86 (3H, s), 3.47 (1H,d, J=12.2 Hz), 2.96 (3H, m), 2.65 (1H, d, J=12.2 Hz), 2.22-1.25 (16H,m); LC/MS (98%, t_(r)=1.77 min), m/z=399.0 [M+H]⁺ (Calc: 398.2).

Heterocyclic-Substituted Piperidine Compound 84 was prepared in a mannersimilar to Example 29 except that Heterocyclic-Substituted PiperidineCompound 83 was used in place of Heterocyclic-Substituted PiperidineCompound 81.

The identity of Heterocyclic-Substituted Piperidine Compound 84,5-(1-cyclooctylpiperidin-4-yl)-7-methoxy-1H-pyrido[2,3-b][1,4]diazepine-2,4(3H,5H)-dione,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 84: ¹H NMR: δ_(H)(DMSO-d₆): 10.22 (1H, s), 7.51 (1H, d, J=8.6 Hz), 6.79 (1H, d, J=8.6Hz), 4.22 (1H, m), 3.86 (3H, s), 3.46 (1H, d, J=11.7 Hz), 2.97 (1H, d,J=11.7 Hz), 2.76-2.53 (3H, m), 2.20 (2H, m), 1.99-1.23 (18H, m); LC/MS(100%, t_(r)=1.81 min), m/z=401.2 [M+H]⁺ (Calc: 400.3).

5.31 Example 31

To a mixture of cyclooctanone (EA, 17 g, 135 mmol, Sigma-Aldrich) inethanol (200 mL) and water (200 mL) were added KCN (17.5 g, 269 mmol,Sigma-Aldrich) followed by ammonium carbonate ([NH₄]₂CO₃, 51.8 g, 539mmol, Sigma-Aldrich). The resulting reaction mixture was stirred at 80°C. for 6 h. The reaction mixture was evaporated to dryness under reducedpressure to provide a white solid precipitate which was filtered,collected, and dried for 16 h to provide 15.9 g of the compound offormula RB, 1,3-diazaspiro[4.7]dodecane-2,4-dione (yield 73%).

A mixture of the compound of formula RB (15.9 g, 8 mmol) in 2N NaOH wasrefluxed for 96 h. The reaction mixture was neutralized by the additionof 2N HCl to provide a white solid precipitate which was filtered andcollected to provide the compound of formula RC,1-aminocyclooctanecarboxylic acid. The compound of formula RC wasdissolved with hot phenylmethanol (i.e., benzyl alcohol, Sigma-Aldrich)then concentrated HCl was added. The resulting reaction mixture wasrefluxed for 16 h. After neutralizing the reaction mixture with 2N NaOH,the resulting mixture was extracted three times with 4:1 CHCl₃:MeOH. Theorganic portions were combined, washed with water, washed with brine,dried (MgSO₄), filtered, and concentrated under reduced pressure toprovide 920 mg of the compound of formula RD, benzyl1-aminocyclooctanecarboxylate (yield 6% for two steps).

A mixture of the compound of formula RE (1-benzylpiperidin-4-one, 1.49mol, Sigma-Aldrich) and acetone (1 L) was cooled to 0° C. Methyl iodide(94.4 mL, 1.51 mol) was added dropwise over 30 min and the resultingreaction mixture was stirred for 3 h, then filtered. The filter cake wasdried under reduced pressure for 18 h to provide the compound of formulaRF as a solid.

At a temperature of 90° C., a mixture of the compound of formula RF (10mmol), MeOH (6 mL) and water (20 mL) was added dropwise to a mixture ofthe compound of formula RD (10 mmol), K₂CO₃ (1 mmol), MeOH (10 mL) andwater (4 mL) over 20 min. The resulting reaction mixture was stirred at90° C. for 48 h. After concentration under reduced pressure, the mixturewas extracted three times with a mixture of EtOAc and water. The organiclayers were combined, dried (MgSO₄), and concentrated under reducedpressure to provide a yellow oil. The resulting oil was chromatographedwith a silica gel column eluted with a gradient of from 10%:90%EtOAc:n-hexane to 50%:50% EtOAc:n-hexane to provide the compound offormula RG, benzyl 1-(4-oxopiperidin-1-yl)cyclooctanecarboxylate.

Sodium triacetoxyborohydride (50 mmol) was added to a mixture of thecompound of formula RG (12.8 mmol), and o-phenylenediamine (3 g, 27.8mmol) in 100 mL of CH₂Cl₂ at a temperature of about 25° C. Thereafter, 3mL of acetic acid was added. The resulting mixture was stirred at atemperature of about 25° C. for about 16 h. MeOH (2 mL) and water (25mL) were added and the mixture was neutralized with 28% aqueous ammoniato adjust the pH to about 8. The organic layer was separated, washedwith brine (10 mL), concentrated under reduced pressure, andchromatographed with a silica gel column eluted with 10:1:1EtOAc:MeOH:TEA to provide the compound of formula RH, benzyl1-(4-(2-aminophenylamino)piperidin-1-yl)cyclooctanecarboxylate.

A mixture of the compound of formula RH in 20 mL of diethyl oxalate washeated at 140° C. for 16 h. After cooling to a temperature of about 25°C., the reaction mixture was diluted with EtOAc, washed with 2N aqueousNaOH (30 mL), washed with brine (20 mL), concentrated under reducedpressure, and chromatographed with a silica gel column eluted with5:5:0.5:0.5 EtOAc:hexane:MeOH:TEA to provide Heterocyclic-SubstitutedPiperidine Compound 88.

The identity of Heterocyclic-Substituted Piperidine Compound 88, benzyl1-(4-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)cyclooctanecarboxylate,was confirmed using ¹H NMR and LC/MS.

Heterocyclic-Substituted Piperidine Compound 88: ¹H NMR: δ_(H) (300 MHz,DMSO-d₆): 11.51 (1H, s), 7.47 (1H, d, J=8.1 Hz), 7.41-7.33 (5H, m),7.24-7.17 (3H, m), 5.17 (2H, s), 4.58 (1H, br), 3.24 (2H, d, J=11.1 Hz),2.76 (2H, d, J=9.3 Hz), 2.33 (2H, t, J=10.8 Hz), 2.01-1.47 (16H, m);LC/MS (100%, t_(r)=1.87 min), m/z=490.2 [M+H]⁺ (Calc: 489.3).

Alternatively, the compound of formula RD was prepared by the followingroute.

To a mixture of the hydrochloride of the compound of formula RC (414 mg,2.00 mmol), aqueous 1N NaOH (4 mL, 4.00 mmol), and dioxane (4 mL) at atemperature of about 25° C. was added (BOC)₂O (0.51 mL, 2.2 mmol). Afterthe addition, the reaction mixture was stirred for 18 h at a temperatureof about 25° C. The mixture was quenched by pouring it into aqueous 1NHCl and extracted with CHCl₃. The organic portion was dried (Na₂SO₄) andconcentrated under reduced pressure to provide a white solid. The solidwas triturated with iso-propyl ether and collected to provide 221 mg ofthe compound of formula RI as a colorless solid (yield 41%).

The identity of the compound of formula RI,1-(tert-butoxycarbonylamino)cyclooctanecarboxylic acid, was confirmedusing ¹H NMR.

Compound RI: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 12.01 (1H, s), 6.90 (1H,s), 1.89-1.45 (14H, m), 1.35 (9H, s).

To a mixture of the compound of formula RI (215 mg, 0.792 mmol) in DMF(1 mL) at a temperature of about 25° C. was added the compound offormula IB (0.103 mmol, 0.871 mmol) and DIEA (0.166 mL, 0.950 mmol).After the addition, the reaction mixture was stirred for 20 h at atemperature of about 25° C. The mixture was quenched by pouring it intowater. A white precipitate formed. The precipitate was collected, washedwith dilute aqueous NaHCO₃, and washed with water to provide 240 mg ofthe compound of formula RJ as a white solid (yield 84%).

The identity of the compound of formula RJ, benzyl1-(tert-butoxycarbonylamino)cyclooctanecarboxylate, was confirmed using¹H NMR.

Compound RJ: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.37-7.34 (5H, m), 5.16(2H, s), 4.69 (1H, s), 2.08-2.04 (4H, m), 1.57 (10H, d, J=8.06 Hz), 1.43(9H, s).

To a suspension of the compound of formula RJ in 1,4-dioxane (4 mL) andMeOH (1 mL) was added 4N HCl in 1,4-dioxane (2 mL) at a temperature ofabout 25° C. The reaction mixture was stirred at 25° C. for 1 h. Theresulting precipitate was filtered, washed with diethyl ether (3 mL),and dried under reduced pressure at 70° C. to provide the compound offormula RD as a solid (yield >98%).

The identity of the compound of formula RD was confirmed using ¹H NMR.

Compound RD: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.40-7.34 (5H, m), 5.21(2H, s), 2.06-1.71 (14H, m).

Alternatively, Heterocyclic-Substituted Piperidine Compound 88 wasprepared by the following route.

The compound of formula RG was prepared from the compounds of formula RDand RF in a manner similar to that described above (yield 38%).

The identity of the compound of formula RG was confirmed using ¹H NMR.

Compound RG: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.38-7.36 (5H, m), 5.14(2H, s), 2.92 (4H, t, J=5.62 Hz), 2.39 (4H, t, J=5.79 Hz), 2.00-1.59(14H, m).

The compound of formula RG (48.0 mmol) and tert-butyl2-aminophenylcarbamate (96.0 mmol, Sigma-Aldrich) were suspended in 200mL of CH₂Cl₂. To this mixture, sodium triacetoxyborohydride (30.42 g,144.0 mmol, Sigma-Aldrich) and acetic acid (10 mL) were added. Theseingredients were stirred at a temperature of about 25° C. for 24 h afterwhich the reaction mixture was extracted 10 times with about 200 mL ofwater each time. The organic layer was dried (MgSO₄), filtered, andconcentrated to dryness under reduced pressure to provide the compoundof formula RK as a solid (yield 95%).

The identity of the compound of formula RK, benzyl1-(4-(2-(tert-butoxycarbonylamino)phenylamino)piperidin-1-yl)cyclooctanecarboxylate,was confirmed using ¹H NMR.

Compound RK: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.46-7.37 (5H, m), 7.07(2H, dd, J=12.51 Hz, 6.13 Hz), 6.78-6.71 (2H, m), 6.10 (1H, s), 5.16(3H, s), 3.58 (1H, dd, J=9.65 Hz, 4.95 Hz), 3.19-2.90 (4H, m), 2.41-1.34(18H, m), 2.41 (9H, s).

To a mixture of the compound of formula RK (0.79 mmol) in CH₂Cl₂ (10 mL)at 0° C. was added dropwise over 10 min methyl 2-chloro-2-oxoacetate(0.79 mmol) in CH₂Cl₂ (3 mL). The resulting reaction mixture was stirredat 0° C. for 30 min. After quenching with saturated NaHCO₃ solution, themixture was extracted three times with CHCl₃. Thereafter, the organiclayer was dried (MgSO₄) and concentrated under reduced pressure. At atemperature of about 25° C., the resulting residue was mixed withethanol (4 mL) and the mixture was then added to sodium methoxide (1.09mmol). The reaction mixture was stirred at 70° C. for 1 h. Afterconcentration under reduced pressure, to the resulting residue was addedwater (0.5 mL) and 2N HCl (1 mL). The resulting precipitate wasfiltered, washed with 90%:10% water:MeOH, and dried under reducedpressure at 60° C. for 12 h to provide the compound of formula RL as asolid (yield >98%).

The identity of the compound of formula RL, benzyl1-(4-(N-(2-(tert-butoxycarbonylamino)phenyl)-2-methoxy-2-oxoacetamido)piperidin-1-yl)cyclooctanecarboxylate,was confirmed using ¹H NMR.

Compound RL: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.98 (1H, d, J=5.1 Hz),7.42-7.32 (5H, m), 7.06-7.04 (2H, m), 6.68 (1H, s), 5.10 (2H, s), 4.35(1H, m), 3.49 (3H, s), 3.02 (2H, t, J=10.8 Hz), 2.90 (1H, t, J=6.0 Hz),2.35 (1H, t, J=6.0 Hz), 2.24 (2H, t, J=12.0 Hz), 1.87-1.78 (6H, m),1.51-1.27 (19H, m).

To the compound of formula RL (553 mg, 0.89 mmol) was added 4N HCl inEtOAc (5.5 mL) at 0° C. Thereafter, the reaction mixture was stirred for30 min at a temperature of about 25° C. A white precipitate formed.Saturated aqueous NaHCO₃ (pH>8) was added and the reaction mixture wasstirred for 30 min at a temperature of about 25° C. Thereafter, themixture was extracted twice with CHCl₃ (50 mL for each extraction). Theorganic layers were combined, washed with water, dried (MgSO₄), andconcentrated under reduced pressure to provide a colorless amorphoussolid. The solid was recrystallized from a mixture of diethyl ether andiso-propyl ether to provide 333 mg of Heterocyclic-SubstitutedPiperidine Compound 88 as a white powder (yield 76%).

5.32 Example 32 In Vitro ORL-1 Receptor Binding Assay

ORL-1 Receptor Binding Assay Procedures: Membranes from recombinantHEK-293 cells expressing the human opioid receptor-like receptor (ORL-1)(Receptor Biology) were prepared by lysing cells in ice-cold hypotonicbuffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish) followedby homogenization with a tissue grinder/Teflon pestle. Membranes werecollected by centrifugation at 30,000×g for 15 min at 4° C. and pelletsresuspended in hypotonic buffer to a final concentration 1-3 mg/mL.Protein concentrations were determined using the BioRad protein assayreagent with bovine serum albumen as standard. Aliquots of the ORL-1receptor membranes were stored at −80° C.

Radioligand binding assays (screening and dose-displacement) used 0.1 nM[³1H]-nociceptin (NEN; 87.7 Ci/mmole) with 10-20 μg membrane protein ina final volume of 500 μL binding buffer (10 mM MgCl₂, 1 mM EDTA, 5%DMSO, 50 mM HEPES, pH 7.4). Non-specific binding was determined in thepresence of 10 nM unlabeled nociceptin (American Peptide Company). Allreactions were performed in 96-deep well polypropylene plates for 1 h atabout 25° C. Binding reactions were terminated by rapid filtration onto96-well Unifilter GF/C filter plates (Packard) presoaked in 0.5%polyethylenimine (Sigma). Harvesting was performed using a 96-welltissue harvester (Packard) followed by three filtration washes with 500μL ice-cold binding buffer. Filter plates were subsequently dried at 50°C. for 2-3 hours. Fifty μL/well scintillation cocktail (BetaScint;Wallac) was added and plates were counted in a Packard Top-Count for 1min/well. The data from screening and dose-displacement experiments wereanalyzed using Microsoft Excel and the curve fitting functions inGraphPad PRISM™, v. 3.0, respectively, or an in-house function forone-site competition curve-fitting.

ORL-1 Receptor Binding Data: Typically, the Heterocyclic-SubstitutedPiperidine Compounds will have a K_(i) (nM) of about 300 or less forbinding to ORL-1 receptors. In one embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) ofabout 100 or less. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds of the invention will have a K_(i) (nM) of about 35or less. In another embodiment, the Heterocyclic-Substituted PiperidineCompounds of the invention will have a K_(i) (nM) of about 20 or less.In another embodiment, the Heterocyclic-Substituted Piperidine Compoundsof the invention will have a K_(i) (nM) of about 15 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have a K_(i) (nM) of about 10 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have a K_(i) (nM) of about 4 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have a K_(i) (nM) of about 1 or less.

In another embodiment, the Heterocyclic-Substituted Piperidine Compoundsof the invention will have a K_(i) (nM) of about 0.4 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have a K_(i) (nM) of about 0.1 or less.

5.33 Example 33 In Vitro ORL-1 Receptor Functional Assay

ORL-1 Receptor [³⁵S]GTPγS Binding Assay Procedures: Membranes fromrecombinant HEK-293 cells expressing the human opioid receptor-like(ORL-1) (Receptor Biology) were prepared by lysing cells in ice-coldhypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish)followed by homogenization with a tissue grinder/Teflon pestle.Membranes were collected by centrifugation at 30,000×g for 15 min at 4°C., and pellets resuspended in hypotonic buffer to a final concentrationof 1-3 mg/mL. Protein concentrations were determined using the BioRadprotein assay reagent with bovine serum albumen as a standard. Aliquotsof the ORL-1 receptor membranes were stored at −80° C.

Functional binding assays were conducted as follows. ORL-1 membranesolution was prepared by sequentially adding final concentrations of0.0664 g/mL ORL-1 membrane protein, 10 μg/mL saponin, 3 μM GDP and 0.20nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂, mM HEPES, pH7.4) on ice. The prepared membrane solution (190 μL/well) wastransferred to 96-shallow well polypropylene plates containing 10 μL of20× concentrated stock solutions of agonist/nociceptin prepared in DMSO.Plates were incubated for 30 min at about 25° C. with shaking. Reactionswere terminated by rapid filtration onto 96-well Unifilter GF/B filterplates (Packard) using a 96-well tissue harvester (Packard) and followedby three filtration washes with 200 μL ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently driedat 50° C. for 2-3 hours. Fifty μL/well scintillation cocktail(BetaScint; Wallac) was added and plates were counted in PackardTop-Count for 1 min/well. Data are analyzed using the sigmoidaldose-response curve fitting functions in GraphPad PRISM v. 3.0, or anin-house function for non-linear, signioidal dose-responsecurve-fitting.

ORL-1 Receptor Functional Data: ORL-1 GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at anORL-1 receptor. Heterocyclic-Substituted Piperidine Compounds typicallywill have an ORL-1 GTP EC₅₀ (nM) of about 5000 or less to stimulateORL-1 receptor function. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds of the invention will have an ORL-1 GTP EC₅₀ (nM)of about 1000 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of about 100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of about 80 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of about 50 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of about 35 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of about 15 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havean ORL-1 GTP EC₅₀ (nM) of about 10 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 4 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 1 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 0.4 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 0.1 or less.

ORL-1 GTP Emax (%) is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist.Typically, the Heterocyclic-Substituted Piperidine Compounds of theinvention will have an ORL-1 GTP Emax (%) of greater than about 50%. Inone embodiment, the Heterocyclic-Substituted Piperidine Compounds willhave an ORL-1 GTP Emax (%) of greater than about 75%. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havean ORL-1 GTP Emax (%) of greater than about 85%. In another embodiment,the Heterocyclic-Substituted Piperidine Compounds will have an ORL-1GTP. Emax (%) of greater than about 95%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have an ORL-1 GTPEmax (%) of about 100% or greater. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have an ORL-1 GTPEmax (%) of about 110% or greater.

5.34 Example 34 In Vitro μ-Opioid Receptor Binding Assays

μ-opioid Receptor Binding Assay Procedures: Radioliganddose-displacement binding assays for μ-opioid receptors used 0.2 nM[³H]-diprenorphine (NEN, Boston, Mass.), with 5-20 mg membraneprotein/well in a final volume of 500 μL binding buffer (10 mM MgCl₂, 1mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were carried out inthe absence or presence of increasing concentrations of unlabelednaloxone. All reactions were conducted in 96-deep well polypropyleneplates for 1-2 h at about 25° C. Binding reactions were terminated byrapid filtration onto 96-well Unifilter GF/C filter plates (Packard,Meriden, Conn.) presoaked in 0.5% polyethylenimine using a 96-welltissue harvester (Brandel, Gaithersburg, Md.) followed by performingthree filtration washes with 500 μL of ice-cold binding buffer. Filterplates were subsequently dried at 50° C. for 2-3 hours. BetaScintscintillation cocktail (Wallac, Turku, Finland) was added (50 L/well),and plates were counted using a Packard Top-Count for 1 min/well. Thedata were analyzed using the one-site competition curve fittingfunctions in GraphPad PRISM v. 3.0 (San Diego, Calif.), or an in-housefunction for one-site competition curve-fitting.

β-opioid Receptor Binding Data: Generally, the lower the K_(i) value,the more effective the Heterocyclic-Substituted Piperidine Compoundswill be at treating pain or diarrhea. Typically, theHeterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM) ofabout 3000 or less for binding to β-opioid receptors. In one embodiment,the Heterocyclic-Substituted Piperidine Compounds will have a K_(i) (nM)of about 1000 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea K_(i) (mM) of about 650 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea K_(i) (nM) of about 525 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea K_(i) (nM) of about 250 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea K_(i) (mM) of about 100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea K_(i) (nM) of about 10 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea K_(i) (DM) of about 1 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea K_(i) (nM) of about 0.1 or less.

5.35 Example 35 In Vitro μ-Opioid Receptor Functional Assays

μ-Opioid Receptor Functional Assay Procedures: [³⁵S]GTPγS functionalassays were conducted using freshly thawed Preceptor membranes. Assayreactions were prepared by sequentially adding the following reagents tobinding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice(final concentrations indicated): membrane protein (0.026 mg/mL),saponin (10 mg/mL), GDP (3 mM) and [³⁵S]GTPγS (0.20 nM; NEN). Theprepared membrane solution (190 μL/well) was transferred to 96-shallowwell polypropylene plates containing 10 μL of 20× concentrated stocksolutions of the agonist DAMGO ([D-Ala2, N-methyl-Phe4Gly-ol5]-enkephalin) prepared in dimethyl sulfoxide (DMSO). Plates wereincubated for 30 min at about 25° C. with shaking. Reactions wereterminated by rapid filtration onto 96-well Unifilter GF/B filter plates(Packard, Meriden, Conn.) using a 96-well tissue harvester (Brandel,Gaithersburg, Md.) followed by three filtration washes with 200 μL ofice-cold wash buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filterplates were subsequently dried at 50° C. for 2-3 h. BetaScintscintillation cocktail (Wallac, Turku, Finland) was added (50 μL/well)and plates were counted using a Packard Top-Count for 1 min/well. Datawere analyzed using the sigmoidal dose-response curve fitting functionsin GraphPad PRISM v. 3.0, or an in-house function for non-linear,sigmoidal dose-response curve-fitting.

μ-Opioid Receptor Functional Data: μ GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at aμ-opioid receptor. Heterocyclic-Substituted Piperidine Compoundstypically will have a μ GTP EC₅₀ (nM) of about 5000 or less to stimulateμ-opioid receptor function. In one embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP EC₅₀ (nM) of about 4100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP EC₅₀ (nM) of about 3100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP EC₅₀ (nM) of about 2000 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP EC₅₀ (nM) of about 1000 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP EC₅₀ (nM) of about 100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP EC₅₀ (nM) of about 10 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP EC₅₀(nM) of about 1 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP EC₅₀(nM) of about 0.4 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP EC₅₀(nM) of about 0.1 or less.

μ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by DAMGO, a standard μ agonist. Generally, the μ GTPEmax (%) value measures the efficacy of a compound to treat or prevent aCondition such as pain or diarrhea. Typically, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea μ GTP Emax (%) of greater than about 10%. In one embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of greater than about 20%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a 4 GTP Emax (%)of greater than about 50%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of greater than about 65%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of greater than about 75%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of greater than about 88%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a μ GTP Emax (%)of about 100% or greater.

5.36 Example 36 In Vitro μ-Opioid Receptor Binding Assays

κ-opioid Receptor Binding Assay Procedures: Membranes from recombinantHEK-293 cells expressing the human kappa opioid receptor (kappa) (clonedin house) were prepared by lysing cells in ice cold hypotonic buffer(2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish) followed byhomogenization with a tissue grinder/Teflon pestle. Membranes werecollected by centrifugation at 30,000×g for 15 min at 4° C. and pelletsresuspended in hypotonic buffer to a final concentration of 1-3 mg/mL.Protein concentrations were determined using the BioRad protein assayreagent with bovine serum albumen as a standard. Aliquots of kappareceptor membranes were stored at −80° C.

Radioligand dose displacement assays used 0.4-0.8 nM [³H]-U69,593 (NEN;40 Ci/mmole) with 10-20 μg membrane protein (recombinant kappa opioidreceptor expressed in HEK 293 cells; in-house prep) in a final volume of200 μL binding buffer (5% DMSO, 50 mM Trizma base, pH 7.4). Non-specificbinding was determined in the presence of 10 μM unlabeled naloxone orU69,593. All reactions were performed in 96-well polypropylene platesfor 1 h at a temperature of about 25° C. Binding reactions weredetermined by rapid filtration onto 96-well Unifilter GF/C filter plates(Packard) presoaked in 0.5% polyethylenimine (Sigma). Harvesting wasperformed using a 96-well tissue harvester (Packard) followed by fivefiltration washes with 200 μL ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 1-2 hours. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

κ-opioid Receptor Binding Data: Typically, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (nM) of about 10,000 or less for Kreceptors. In one embodiment, the Heterocyclic-Substituted PiperidineCompounds will have a Ki (nM) of about 5000 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea Ki (nM) of about 1000 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a Ki (DM) ofabout 500 or less. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (nM) of about 300 or less. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a Ki (nM) of about 200 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a Ki (nM) ofabout 100 or less. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (nM) of about 50 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea Ki (nM) of about 20 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a Ki (nM) ofabout 15 or less. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (mM) of about 10 or less.

5.37 Example 37 In Vitro κ-Opioid Receptor Functional Assays

κ-Opioid Receptor Functional Assay Procedures: Functional [³⁵S]GTPγSbinding assays were conducted as follows. Kappa opioid receptor membranesolution was prepared by sequentially adding final concentrations of0.026 μg/mL kappa membrane protein (in-house), 10 μg/mL saponin, 3 μMGDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂,20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190μL/well) was transferred to 96-shallow well polypropylene platescontaining 10 μL of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at a temperature of about 25°C. with shaking. Reactions were terminated by rapid filtration onto96-well Unifilter GF/B filter plates (Packard) using a 96-well tissueharvester (Packard) and followed by three filtration washes with 200 μLice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filterplates were subsequently dried at 50° C. for 2-3 hours. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Functional Data: κ GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at a κreceptor. Heterocyclic-Substituted Piperidine Compounds typically willhave a κ GTP EC₅₀ (nM) of about 10,000 or less to stimulate κ opioidreceptor function. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a κ GTP EC₅₀ (nM) of about 5000 or less.In another embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a κ GTP EC₅₀ (nM) of about 2000 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea κ GTP EC₅₀ (nM) of about 1500 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 800 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 500 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 300 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 50 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 25 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 10 or less.

κ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by U69,593. Typically, the Heterocyclic-SubstitutedPiperidine Compounds of the invention have a K GTP Emax (%) of greaterthan about 15%. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds have a κ GTP Emax (%) of greater than about 30%. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundshave a κ GTP Emax (%) of greater than about 40%. In another embodiment,the Heterocyclic-Substituted Piperidine Compounds have a κ GTP Emax (%)of greater than about 45%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds have a κ GTP Emax (%) ofgreater than about 55%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds have a κ GTP Emax (%) ofgreater than about 75%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds have a κ GTP Emax (%) ofgreater than about 90%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds have a κ GTP Emax (%) ofabout 100% or greater.

5.38 Example 38 In Vitro δ-Opioid Receptor Binding Assays

δ-opioid Receptor Binding Assay Procedures: Radioliganddose-displacement assays used 0.2 nM [³H]-Naltrindole (NEN; 33.0Ci/mmole) with 10-20 μg membrane protein (recombinant delta opioidreceptor expressed in CHO-K1 cells; Perkin Elmer) in a final volume of500 μL binding buffer (5 mM MgCl₂, 5% DMSO, 50 mM Trizma base, pH 7.4).Non-specific binding was determined in the presence of 25 μM unlabelednaloxone. All reactions were performed in 96-deep well polypropyleneplates for 1 h at a temperature of about 25° C. Binding reactions weredetermined by rapid filtration onto 96-well Unifilter GF/C filter plates(Packard) presoaked in 0.5% polyethylenimine (Sigma). Harvesting wasperformed using a 96-well tissue harvester (Packard) followed by fivefiltration washes with 500 μL ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 1-2 hours. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

δ-opioid Receptor Binding Data: Typically, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (nM) of about 10,000 or less for δreceptors. In one embodiment, the Heterocyclic-Substituted PiperidineCompounds will have a Ki (nM) of about 9000 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea Ki (nM) of about 7500 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a Ki (nM) ofabout 6500 or less. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (mM) of about 5000 or less. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a Ki (nM) of about 3000 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a Ki (nM) ofabout 2500 or less. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (nM) of about 1000 or less. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a Ki (nM) of about 500 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a Ki (nM) ofabout 350 or less. In another embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a Ki (nM) of about 250 or less. Inanother embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a Ki (nM) of about 100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a Ki (nM) ofabout 10 or less.

5.39 Example 39 In Vitro 67-Opioid Receptor Functional Assays

δ-Opioid Receptor Functional Assay Procedures: Functional [³⁵S]GTPγSbinding assays were conducted as follows. Delta opioid receptor membranesolution was prepared by sequentially adding final concentrations of0.026 μg/μL delta membrane protein (Perkin Elmer), 10 μg/mL saponin, 3μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190μL/well) was transferred to 96-shallow well polypropylene platescontaining 10 μL of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at a temperature of about 25°C. with shaking. Reactions were terminated by rapid filtration onto96-well Unifilter GF/B filter plates (Packard) using a 96-well tissueharvester (Packard) and followed by three filtration washes with 200 μLice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filterplates were subsequently dried at 50° C. for 1-2 hours. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-count for 1 min/well.

δ-Opioid Receptor Functional Data: δ GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at a 6receptor. Heterocyclic-Substituted Piperidine Compounds typically willhave a δ GTP EC₅₀ (nM) of about 10,000 or less to stimulate 6 opioidreceptor function. In one embodiment, the Heterocyclic-SubstitutedPiperidine Compounds will have a δ GTP EC₅₀ (nM) of about 3500 or less.In another embodiment, the Heterocyclic-Substituted Piperidine Compoundswill have a δ GTP EC₅₀ (nM) of about 1000 or less. In anotherembodiment, the Heterocyclic-Substituted Piperidine Compounds will havea δ GTP EC₅₀ (mM) of about 500 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 100 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 90 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 50 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 25 or less. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 10 or less.

δ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by met-enkephalin. Typically, theHeterocyclic-Substituted Piperidine Compounds of the invention will havea δ GTP Emax (%) of greater than about 10%. In one embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of greater than about 30%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of greater than about 50%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of greater than about 75%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a 6 GTP Emax (%)of greater than about 90%. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of about 100% or greater. In another embodiment, theHeterocyclic-Substituted Piperidine Compounds will have a δ GTP Emax (%)of about 110% or greater.

5.40 Example 40 Efficacy of Receptor Binding and Activity Response

The following Tables provide results on the efficacy of binding andactivity response of several Heterocyclic-Substituted PiperidineCompounds to the ORL-1 receptor and, for certainHeterocyclic-Substituted Piperidine Compounds, the μ opioid receptor,the κ opioid receptor and/or the δ opioid receptor.

In Table 1, binding efficacy to the ORL-1 receptor was determined by theprocedure in Example 32. Binding efficacy to the μ opioid receptor wasdetermined by the procedure in Example 34. Binding efficacy to the κopioid receptor was determined by the procedure in Example 36. Bindingefficacy to the δ opioid receptor was determined by the procedure inExample 38.

In Table 2, activity response to the ORL-1 receptor was determined bythe procedure in Example 33. Activity response to the μ opioid receptorwas determined by the procedure in Example 35. Activity response to theκ opioid receptor was determined by the procedure in Example 37.Activity response to the δ opioid receptor can be determined by theprocedure in Example 39.

TABLE 1 Efficacy of Receptor Binding of Heterocyclic-SubstitutedPiperidine Compounds K_(i) [Average ± Std Deviation] (nM) Ref. OpioidReceptor No. Compound ORL-1 μ κ Δ 6

  65 ± 26   2200 ± 300  167 ± 6   2900 ± 235 18

 63.2 ± 2.5 17

 11.5 ± 1.0   2500 ± 525 9

 22.8 ± 8.5   825 ± 30  880 ± 80   9600 ± 2600 12

  8.9 ± 0.2   1300 ± 2200  439 ± 6   4050 ± 400 24

 453 ± 32   3300 ± 715 6950 ± 1350   5450 ± 1400 5

 35.5 ± 7.5 13,700 ± 3800  355 ± 30 16,200 ± 3250 20

 229 ± 12 16

 32.6 ± 1.6   3800 ± 1150 7

 620 ± 56   6200 ± 1300 10

 610 ± 65   2950 ± 325 11

 1550 ± 285   5000 ± 375 85

39930 43

 291 ± 20  >10⁶ 44

  52 ± 8   9540 ± 2122 4232 ± 739 65660 29

 1526 ± 219 66

  89 ± 22  17385 ± 2235 1317 ± 148 54760 47

 584 ± 104 28200  559 ± 75 52100 78

 1762 ± 226 79

 1965 ± 750 56

  4 ± 0.1   529 ± 127 20800 57

  13 ± 4   769 ± 6  170 ± 21 21900 67

  51 ± 6 12380 72400 86

 >10⁶ 60

  5.6 ± 0.4   1380 ± 515  119 ± 4 23400 61

  56 ± 6  15750 ± 1550  682 ± 106 22800 58

 173 ± 49  11930 ± 2620 81

16500 ± 1550 83

 6010 ± 686 87

  68 ± 6  11670 ± 1200 80

 1770 ± 50

TABLE 2 Activity Response of Heterocyclic-Substituted PiperidineCompounds GTP EC₅₀ (nM) GTP Emax (%) Ref. Opioid Receptor OpioidReceptor No. Compound ORL-1 μ κ ORL-1 μ κ 6

 240 ± 115  590 ± 180 87.3 ± 5.3 13.7 ± 0.9 18

 183 ± 14.5 60.3 ± 4.6 17

 11.5 ± 1.0 2500 ± 525   74 ± 16 9

 208 ± 8.6 3924 ± 13  4050 ± 670   68 ± 1.0 28.5 ± 2.6 22.5 ± 2.6 12

 31.9 ± 3.5 1640 ± 440  7000 ± 345  132 ± 8.5 66.0 ± 0.7 57.7 ± 4.3 24

5250 ± 465  152 ± 18 5

 166 ± 34  1290 ± 220 55.8 ± 3.8  114 ± 8.7 20

 770 ± 43 39.3 ± 0.9 16

 153 ± 22 55.0 ± 4.2 7

1300 ± 175 41.3 ± 9.8 10

1400 ± 125 45.3 ± 1.8 43

 450 ± 47  27 44

 141 ± 27  46 66

 202 ± 37  38 47

7800 ± 1600 13992 ± 2370  90 25 56

 25 ± 7  44 57

 96 ± 23  4800 ± 700  53 28 67

 574 ± 39  40 60

 36 ± 19  460 ± 70  62 17 61

 830 ± 125  6460 ± 500  82 22 58

 168 ± 12  22 87

1550 ± 140 135

5.41 Example 41 In Vivo Assays for Prevention or Treatment of Pain

Test Animals Each experiment uses rats weighing between 200-260 g at thestart of the experiment. The rats are group-housed and have free accessto food and water at all times, except prior to oral administration of aHeterocyclic-Substituted Piperidine Compound when food is removed for 16hours before dosing. A control group acts as a comparison to ratstreated with a Heterocyclic-Substituted Piperidine Compound. The controlgroup is administered the carrier for the Heterocyclic-SubstitutedPiperidine Compound. The volume of carrier administered to the controlgroup is the same as the volume of carrier and Heterocyclic-SubstitutedPiperidine Compound administered to the test group.

Acute Pain: To assess the actions of a Heterocyclic-SubstitutedPiperidine Compound for the treatment or prevention of acute pain, therat tail flick test can be used. Rats are gently restrained by hand andthe tail exposed to a focused beam of radiant heat at a point 5 cm fromthe tip using a tail flick unit (Model 7360, commercially available fromUgo Basile of Italy). Tail flick latencies are defined as the intervalbetween the onset of the thermal stimulus and the flick of the tail.Animals not responding within 20 seconds are removed from the tail flickunit and assigned a withdrawal latency of 20 seconds. Tail flicklatencies are measured immediately before (pretreatment) and 1, 3, and 5hours following administration of a Heterocyclic-Substituted PiperidineCompound. Data are expressed as tail flick latency(s) and the percentageof the maximal possible effect (% MPE), i.e., 20 seconds, is calculatedas follows:

${\%\mspace{14mu}{MPE}} = {\frac{\begin{bmatrix}{( {{post}\mspace{14mu}{administration}\mspace{14mu}{latency}} ) -} \\( {{pre}\text{-}{administration}\mspace{14mu}{latency}} )\end{bmatrix}}{( {20\; s\mspace{14mu}{pre}\text{-}{administration}\mspace{14mu}{latency}} )} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

Acute pain can also be assessed by measuring the animal's response tonoxious mechanical stimuli by determining the paw withdrawal threshold(“PWT”), as described below.

Inflammatory Pain: To assess the actions of a Heterocyclic-SubstitutedPiperidine Compound for the treatment or prevention of inflammatorypain, the Freund's complete adjuvant (“FCA”) model of inflammatory painis used. FCA-induced inflammation of the rat hind paw is associated withthe development of persistent inflammatory mechanical hyperalgesia andprovides reliable prediction of the anti-hyperalgesic action ofclinically useful analgesic drugs (L. Bartho et al., “Involvement ofCapsaicin-sensitive Neurones in Hyperalgesia and Enhanced OpioidAntinociception in Inflammation,” Naunyn-Schmiedeberg's Archives ofPharmacol. 342:666-670 (1990)). The left hind paw of each animal isadministered a 50 μL intraplantar injection of 50% FCA. 24 hour postinjection, the animal is assessed for response to noxious mechanicalstimuli by determining the PWT, as described below. Rats are thenadministered a single injection of 1, 3, 10 or 30 mg/kg of either aHeterocyclic-Substituted Piperidine Compound; 30 mg/kg of a controlselected from Celebrex, indomethacin or naproxen; or carrier. Responsesto noxious mechanical stimuli are then determined 1, 3, 5 and 24 hourspost administration. Percentage reversal of hyperalgesia for each animalis defined as:

${\%\mspace{14mu}{Reversal}} = {\frac{\begin{bmatrix}{( {{post}\mspace{14mu}{administration}\mspace{14mu}{PWT}} ) -} \\( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} )\end{bmatrix}}{\lbrack {( {{baseline}\mspace{14mu}{PWT}} ) - ( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} )} \rbrack} \times 100}$

Neuropathic Pain To assess the actions of a Heterocyclic-SubstitutedPiperidine Compound for the treatment or prevention of neuropathic pain,either the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration for rear paw of the animal.Percentage reversal of neuropathic hyperalgesia is defined as:

${\%\mspace{14mu}{Reversal}} = {\frac{\begin{bmatrix}{( {{post}\mspace{14mu}{administration}\mspace{14mu}{PWT}} ) -} \\( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} )\end{bmatrix}}{\lbrack {( {{baseline}\mspace{14mu}{PWT}} ) - ( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} )} \rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered aHeterocyclic-Substituted Piperidine Compound for the left rear paw ofthe animal. The animal can also be assessed for response to noxiousthermal stimuli or for tactile allodynia, as described below. The Chungmodel for neuropathic pain is described in S. H. Kim, “An ExperimentalModel for Peripheral Neuropathy Produced by Segmental Spinal NerveLigation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy) as described inC. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). Themaximum weight that can be applied to the hind paw is set at 250 g andthe end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and either only theaffected (ipsilateral) paw is tested, or both the ipsilateral andcontralateral (non-injured) paw are tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperaleesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by K. Hargreaveset al., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Either onlythe affected (ipsilateral) paw is tested, or both the ipsilateral andcontralateral (non-injured) paw are tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, plexiglass compartments with a wire mesh floor andallowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference for all purposes.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof wherein: each R₂ isindependently selected from: (a) -halo, —CN, —NO₂, —OT₃, —C(O)T₃,—C(O)OT₃, —C(O)N(T₁)(T₂), —S(O)₂OH, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂),—N(T₁)(T₂), —N(T₃)C(O)T₃, —N(T₃)C(O)N(T₁)(T₂), —N(T₃)S(O)₂T₃, and—N(T₃)S(O)₂N(T₁)(T₂); or (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl,—(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or6-membered)heterocycle, and -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with 1, 2, or 3 independentlyselected R₈ groups; or (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5-or 6-membered)heteroaryl, each of which is unsubstituted or substitutedwith 1, 2, or 3 independently selected R₇ groups; a is an integerselected from 0, 1, and 2; R₃ is selected from: (a) —H; or (b)—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —O(C₁-C₆)alkyl,—O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl,—(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,—(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,—(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, and -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R₈ groups; or (c)-phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to 10-membered)heteroaryl,each of which is unsubstituted or substituted with 1, 2, or 3independently selected R₇ groups; or (d) —(C₁-C₆)alkyl(═O)W₁,—(C₁-C₆)alkyl(═NH)W₁, —C(O)OV₁, —C(O)N(V₁)₂, —S(O)₂N(V₁)₂, and—S(O)₂(C₁-C₆)alkyl; or (e) —(C₁-C₄)alkyl substituted with 1, 2, or 3substituents independently selected from —(C₃-C₇)cycloalkyl,—(C₃-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,—(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,—(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7- to10-membered)bicycloheterocycle, -phenyl, -naphthalenyl, —(C₁₄)aryl, and-(5- to 10-membered)heteroaryl; or (f) —(C₁-C₃)alkyl substituted with asubstituent selected from —N(R₆)₂, —S(O)₂N(V₁)₂, —N(R₉)C(O)W₁,—N(R₉)S(O)₂W₁, and —C(O)N(V)₂; each W₁ is independently selected from:(a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, and —N(R₆)₂; or (b) -(5- or6-membered)heteroaryl optionally substituted with 1, 2, or 3independently selected —(C₁-C₆)alkyl; each V₁ is independently selectedfrom —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl, and -benzyl; each Yis independently selected from O and S; A and B are independentlyselected from: (a) —H, —CN, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, and —(C₁-C₆)alkoxy, each of which—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl is unsubstituted or substituted with1 or 2 substituents independently selected from —OH, —S(O)₂NH₂, —N(R₆)₂,═NR₆, —C(O)OT₃, —C(O)N(R₆)₂, —N(R₆)C(O)R₉, and -(5- or6-membered)heterocycle or 1, 2, or 3 independently selected -halo; or(b) A-B together form a (C₂-C₆)bridge, which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R₈ groups, and whichbridge optionally contains —HC═CH— within the (C₂-C₆)bridge; wherein thepiperazine ring that is fused to the phenyl group can be in the endo- orexo-conformation with respect to the A-B bridge; or (c) A-B togetherform a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge; wherein the piperazine ring that is fused to the phenyl groupcan be in the endo- or exo-conformation with respect to the A-B bridge;R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), and—(CH₂)₂—N(R_(c))S(O)₂—R_(c); R_(b) is selected from: (a) —H,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to 7-membered)heterocycle,—N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl, and —N(R_(c))—(3- to7-membered)heterocycle; or (b) -phenyl, -naphthalenyl, and -(5- or6-membered)heteroaryl, each of which is unsubstituted or substitutedwith 1, 2, or 3 independently selected R₇ groups; or (c)—N(R_(c))-phenyl, —N(R_(c))-naphthalenyl, —N(R_(c))—(C₁₄)aryl, and—N(R_(c))—(5- to 10-membered)heteroaryl, each of which is unsubstitutedor substituted with 1, 2, or 3 independently selected R₇ groups; eachR_(c) is independently selected from —H and —(C₁-C₄)alkyl; C is selectedfrom —H, -halo, —CN, —OT₃, —C(O)OT₃, —C(O)N(T₁)(T₂),—(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —N(R₆)₂, —N(R₆)C(O)R₉,—NR₆SO₂N(R₆)₂, —NR₆—C(═NR₆)N(R₆)₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and—(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and—(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2 substituentsindependently selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(O)OT₃,—C(O)N(R₆)₂, —N(R₆)C(O)R₉, and -(5- or 6-membered)heterocycle or from 1,2, or 3 independently selected -halo; the dashed line in the piperidineor bridged piperidine central ring denotes the presence or absence of abond, and when the dashed line denotes the presence of a bond then D isabsent, otherwise D is: (a) —H, —CN, —C(O)OT₃, or —C(O)N(T₁)(T₂); or (b)—(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2, or 3independently selected R₈ groups and, optionally, in which any D groupcarbon atom except the carbon atom bonded directly to the piperidine orbridged piperidine central ring, is independently replaced by O or S; or(c) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl, each ofwhich is unsubstituted or substituted with 1, 2, or 3 independentlyselected R₇ groups; Z is a bond; R₁ is selected from:

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, and 7; e and f areeach an integer independently selected from 0, 1, 2, 3, 4, and 5provided that 2≦(e+f)≦5; j and k are each an integer independentlyselected from 0, 1, 2, 3, and 4 provided that 1≦(j+k)≦4; each T₁, T₂,and T₃ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R₈ groups and,optionally, in which any carbon atom is independently replaced by O orS, or T₁ and T₂ together can form a 5- to 8-membered ring where thenumber of atoms in the ring includes the nitrogen atom to which T₁ andT₂ are bonded, said 5- to 8-membered ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R₈ groups and,optionally, any carbon atom in said 5- to 8-membered ring isindependently replaced by O or S; each R₆ is independently selected from—H, —(C₁-C₆)alkyl, and —(C₃-C₇)cycloalkyl, or two R₆ groups attached tothe same nitrogen atom can form a 5- to 8-membered ring, the number ofatoms in the ring including the nitrogen atom, in which one of the ringcarbon atoms is optionally replaced by O or S; each R₇ is independentlyselected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₉,—SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═NR₉,—NR₉OH, —C(O)OR₉, —OC(O)R₉, —OC(O)OR₉, —S(O)R₉, and —S(O)₂R₉; each R₈ isindependently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,oxo, ═S, -phenyl, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH, —C(O)OR₉, —OC(O)R₉,—OC(O)OR₉, —S(O)R₉, and —S(O)₂R₉; each R₉ is independently selected from—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle,—C(halo)₃, —CH(halo)₂, and —CH₂(halo); each p is an integerindependently selected from 0 and 1; R₁₁ is selected from —H, —C(O)OR₉,—C(O)N(R₆)₂, and —(C₁-C₄)alkyl which is unsubstituted or substitutedwith —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(O)OR₉, or —C(O)N(R₆)₂; and eachhalo is independently selected from —F, —Cl, —Br, and —I.
 2. Thecompound of claim 1, wherein each Y is O.
 3. The compound of claim 2,wherein A is H.
 4. The compound of claim 2, wherein B is H.
 5. Thecompound of claim 4, wherein A is H.
 6. The compound of claim 2, whereinC is H.
 7. The compound of claim 2, wherein D is H.
 8. The compound ofclaim 7, wherein C is H.
 9. The compound of claim 2, wherein A, B, C andD are each H, R₃ is —H or methyl substituted by —CN, and a is 0 or 1.10. The compound of claim 1, wherein Z is a bond and —R₁ is selectedfrom:


11. The compound of claim 10, wherein R₁ is selected from formula (i),R₁₁ is —H, m is 3, p is 1, and R₈ is —(C₁-C₄)alkyl.
 12. The compound ofclaim 11, wherein R₈ is iso-propyl.
 13. The compound of claim 10,wherein R₁ is selected from formula (i), R₁₁ is —H, m is 5, and p is 0.14. The compound of claim 10, wherein R₁ is selected from formula (iii),R₁₁ is —H, p is 0, and j+k=1.
 15. The compound of claim 1, wherein a is1 and R₂ is (a) —F, —Cl, —Br, —C(O)T₃, —C(O)OT₃, —S(O)₂T₃, or—N(T₁)(T₂); or (b) -(C₁-C₆)alkyl which is unsubstituted or substitutedwith 1, 2, or 3 independently selected R₈ groups.
 16. The compound ofclaim 15, wherein R₂ is —F, —Cl, or —Br.
 17. The compound of claim 16,wherein R₂ is —F.
 18. The compound of claim 15, wherein T₃ is —CH₃. 19.The compound of claim 1, wherein each R₂ is independently -halo, —OH,—NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₂)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl, or -(5- or6-membered)heteroaryl.
 20. The compound of claim 19, wherein a is 2 andeach R₂ is independently -halo, —OH, —NH₂, —CN, methyl, ethyl, n-propyl,iso-propyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.
 21. Thecompound of claim 20, wherein each R₂ is independently -halo.
 22. Thecompound of claim 19, wherein a is 1 and R₂ is -halo, —OH, —NH₂, —CN,methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl,cycloheptyl, or phenyl.
 23. The compound of claim 22, wherein R₂ is-halo.
 24. The compound of claim 1, wherein A-B together form a(C₂-C₆)bridge, which is unsubstituted or substituted with 1, 2, or 3independently selected R₈ groups, and which bridge optionally contains—HC═CH— within the (C₂-C₆)bridge.
 25. The compound of claim 24, whereinA-B together form a (C₂)bridge, a —HC═CH— bridge, or a (C₃)bridge. 26.The compound of claim 25, wherein R₃ is —H, —(C₁-C₆)alkyl, —(C₁-C₆)alkylsubstituted by an R₈ group, —(C₃-C₇)cycloalkyl, or —(C₃-C₇)cycloalkylsubstituted by an R₈ group.
 27. The compound of claim 26, wherein R₃ is—(C₁-C₆)alkyl.
 28. The compound of claim 27, wherein R₃ is methyl,ethyl, n-propyl or iso-propyl.
 29. The compound of claim 26, wherein R₃is —(C₁-C₆)alkyl substituted by an R₈ group.
 30. The compound of claim29, wherein R₃ is methyl, ethyl, n-propyl or iso-propyl, each of whichis substituted by an R₈ group.
 31. The compound of claim 25, wherein thebridge is unsubstituted.
 32. The compound of claim 1, wherein a is 0.33. The compound of claim 1, wherein D is —CH₃.
 34. The compound ofclaim 1, wherein C is —C(O)OT₃ or —C(O)N(T₁)(T₂).
 35. The compound ofclaim 1, wherein R₃ is selected from: (a) —C(O)OV₁; or (b) —C(O)N(V₁)₂;or (c) —(C₁-C₂)alkyl substituted with a substituent selected from—NHS(O)₂W₁, —C(O)OR₉, and —C(O)N(V₁)₂; or (d) —H.
 36. The compound ofclaim 35, wherein R₃ is —H.
 37. The compound of claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 38. A pharmaceuticallyacceptable salt of the compound of claim 37, wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a p-toluenesulfonic acid-salt.
 39. The compound ofclaim 1, which is a stereoisomer or a tautomer thereof.
 40. The compoundof claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 41. A pharmaceuticallyacceptable salt of the compound of claim 40, wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a p-toluenesulfonic acid-salt.
 42. Apharmaceutically acceptable salt of the compound of claim 1, wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a p-toluenesulfonic acid-salt.
 43. A compositioncomprising an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 44. A method for modulating ORL-1receptor function in a cell, comprising contacting a cell capable ofexpressing the ORL-1 receptor with an effective amount of the compoundor a pharmaceutically acceptable salt of the compound of claim
 1. 45.The method of claim 44, wherein the compound or the pharmaceuticallyacceptable salt of the compound acts as an agonist at the ORL-1 receptoror as an antagonist at the ORL-1 receptor.
 46. A compound of formula:

or a pharmaceutically acceptable salt thereof wherein: R₁ is selectedfrom:

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, and 7; e and f areeach an integer independently selected from 0, 1, 2, 3, 4, and 5provided that 2≦(e+f)≦5; j and k are each an integer independentlyselected from 0, 1, 2, 3, and 4 provided that 1≦(j+k)≦4; each R₆ isindependently selected from —H, —(C₁-C₆)alkyl, and —(C₃-C₇)cycloalkyl,or two R₆ groups attached to the same nitrogen atom can form a 5- to8-membered ring, the number of atoms in the ring including the nitrogenatom, in which one of the ring carbon atoms is optionally replaced by Oor S; each R₈ is independently selected from —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, oxo, ═S, -phenyl, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH,—C(O)OR₉, —OC(O)R₉, —OC(O)OR₉, —S(O)R₉, and —S(O)₂R₉; each R₉ isindependently selected from —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, and—CH₂(halo); each p is an integer independently selected from 0 and 1;R₁₁ is selected from —H, —C(O)OR₉, —C(O)N(R₆)₂, and —(C₁-C₄)alkyl whichis unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂; and each halo is independently selected from—F, —Cl, —Br, and —I.
 47. A pharmaceutically acceptable salt of thecompound of claim 46, wherein the pharmaceutically acceptable salt is ahydrochloride-salt, a sodium-salt, a potassium-salt, or ap-toluenesulfonic acid-salt.
 48. The compound of claim 46, which is astereoisomer or a tautomer thereof.
 49. A composition comprising aneffective amount of the compound or a pharmaceutically acceptable saltof the compound of claim 46 and a pharmaceutically acceptable carrier orexcipient.
 50. A method for modulating ORL-1 receptor function in acell, comprising contacting a cell capable of expressing the ORL-1receptor with an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim
 46. 51. The method of claim 50,wherein the compound or the pharmaceutically acceptable salt of thecompound acts as an agonist at the ORL-1 receptor or as an antagonist atthe ORL-1 receptor.
 52. A compound of formula:

or a pharmaceutically acceptable salt thereof wherein: R₁ is selectedfrom:

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, and 7; e and f areeach an integer independently selected from 0, 1, 2, 3, 4, and 5provided that 2≦(e+f)≦5; j and k are each an integer independentlyselected from 0, 1, 2, 3, and 4 provided that 1≦(j+k)≦4; each R₆ isindependently selected from —H, —(C₁-C₆)alkyl, and —(C₃-C₇)cycloalkyl,or two R₆ groups attached to the same nitrogen atom can form a 5- to8-membered ring, the number of atoms in the ring including the nitrogenatom, in which one of the ring carbon atoms is optionally replaced by Oor S; each R₈ is independently selected from —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, oxo, ═S, -phenyl, -halo, —N₃, —NO₂, —CH═NR₉, —NR₉OH,—C(O)OR₉, —OC(O)R₉, —OC(O)OR₉, —S(O)R₉, and —S(O)₂R₉; each R₉ isindependently selected from —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, and—CH₂(halo); each p is an integer independently selected from 0 and 1;R₁₁ is selected from —H, —C(O)OR₉, —C(O)N(R₆)₂, and —(C₁-C₄)alkyl whichis unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(O)OR₉, or —C(O)N(R₆)₂; and each halo is independently selected from—F, —Cl, —Br, and —I.
 53. A pharmaceutically acceptable salt of thecompound of claim 52, wherein the pharmaceutically acceptable salt is ahydrochloride-salt, a sodium-salt, a potassium-salt, or ap-toluenesulfonic acid-salt.
 54. The compound of claim 52, which is astereoisomer or a tautomer thereof.
 55. A composition comprising aneffective amount of the compound or a pharmaceutically acceptable saltof the compound of claim 52 and a pharmaceutically acceptable carrier orexcipient.
 56. A method for modulating ORL-1 receptor function in acell, comprising contacting a cell capable of expressing the ORL-1receptor with an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim
 52. 57. The method of claim 56,wherein the compound or the pharmaceutically acceptable salt of thecompound acts as an agonist at the ORL-1 receptor or as an antagonist atthe ORL-1 receptor.
 58. A compound of formula (I):

or a pharmaceutically acceptable salt thereof wherein: each R₂ isindependently selected from: (a) -halo, —OH, —NH₂, —CN, or —NO₂; or (b)-(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl,-(5- or 6-membered)heterocycle, -phenyl, -naphthyl, or -(5- or6-membered)heteroaryl, each of which is unsubstituted or substitutedwith 1, 2 or 3 R₈ groups; a is an integer selected from 0, 1, and 2; R₃is selected from: (a) —H; or (b) -(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,—(C₃-C₇)cycloalkyl, —(C₅-C₇)cycloalkenyl, —(C₃-C₇)cycloalkoxy, -(3- to7-membered)heterocycle, -phenyl, -naphthyl, and -(5- to10-membered)heteroaryl, each of which is unsubstituted or substitutedwith 1, 2 or 3 R₈ groups; or (c) —CH₂CH₂OH, —(C₁-C₆)alkyl(═O)W₁,—C(O)OV₁, —C(O)N(V₁)₂, and —S(O)₂(C₁-C₆)alkyl; or (d) -(C₁-C₄)alkylsubstituted with 1, 2 or 3 substituents independently selected from—(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkoxy, -(3- to 7-membered)heterocycle,-phenyl, -naphthyl, and -(5- to 10-membered)heteroaryl; or (e)-(C₁-C₃)alkyl substituted with a substituent selected from —N(R₆)₂,—S(O)₂NH₂, —NHC(O)W₁, —NHS(O)₂W₁, —C(O)OV₁, and —C(O)N(V₁)₂; each W₁ isindependently selected from: (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —CH₂CH₂OH, and —N(R₆)₂; or (b) -(5-or 6-membered)heteroaryl optionally substituted with 1, 2 or 3independently selected —(C₁-C₆)alkyl; each V₁ is independently selectedfrom —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl, and -benzyl; each Yis independently selected from O and S; A and B are independentlyselected from —H, —N(R₆)₂, —(C₃-C₁₂)cycloalkyl, and —(C₁-C₆)alkyl eachof which —(C₁-C₆)alkyl is unsubstituted or substituted with —OH,—S(O)₂NH₂, or from 1 to 3 independently selected -halo, or A-B togetherform a (C₂-C₆)bridge; C is —H; D is —H; the dashed line in thepiperidine or bridged piperidine central ring is absent; Z is a singlebond; R₁ is selected from:

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, and 7 e and f areeach an integer independently selected from 0, 1, 2, 3, 4, and 5provided that 2≦(e+f)≦5; j and k are each an integer independentlyselected from 0, 1, 2, 3, and 4 provided that 1≦(j+k)≦4; each R₆ isindependently selected from —H, —(C₁-C₆)alkyl, and —(C₃-C₇)cycloalkyl,or two R₆ groups attached to the same nitrogen atom can form a 5- to8-membered ring, the number of atoms in the ring including the nitrogenatom, in which one of the ring carbon atoms is optionally replaced by Oor S; each R₈ is independently selected from —(C₁-C₄)alkyl,—O(C₁-C₄)alkyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, and—C(O)OR₉; each R₉ is independently selected from —H, —(C₁-C₆)alkyl,-phenyl, and -benzyl; each p is an integer independently selected from 0and 1; R₁₁ is selected from —H, —(C₁-C₄)alkyl, and -halo; and each halois independently selected from —F, —Cl, —Br, and —I.
 59. The compound ofclaim 58, which is:

or a pharmaceutically acceptable salt thereof.
 60. A pharmaceuticallyacceptable salt of the compound of claim 59, wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a p-toluenesulfonic acid-salt.
 61. The compound ofclaim 58, which is:

or a pharmaceutically acceptable salt thereof.
 62. A pharmaceuticallyacceptable salt of the compound of claim 61, wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a p-toluenesulfonic acid-salt.
 63. Apharmaceutically acceptable salt of the compound of claim 58, whereinthe pharmaceutically acceptable salt is a hydrochloride-salt, asodium-salt, a potassium-salt, or a p-toluenesulfonic acid-salt.
 64. Thecompound of claim 58, which is a stereoisomer or a tautomer thereof. 65.A composition comprising an effective amount of the compound or apharmaceutically acceptable salt of the compound of claim 58 and apharmaceutically acceptable carrier or excipient.
 66. A method formodulating ORL-1 receptor function in a cell, comprising contacting acell capable of expressing the ORL-1 receptor with an effective amountof the compound or a pharmaceutically acceptable salt of the compound ofclaim
 58. 67. The method of claim 66, wherein the compound or thepharmaceutically acceptable salt of the compound acts as an agonist atthe ORL-1 receptor or as an antagonist at the ORL-1 receptor.